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STUDY OBJECTIVE: Alemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such as chronic lymphocytic leukemia, and incorporated into many hematopoietic stem cell transplant (HSCT) conditioning regimens, few studies have evaluated the pharmacology of alemtuzumab in adult patients with sickle cell disease (SCD). We therefore examined the pharmacokinetics (PK) and pharmacodynamics (PD) of alemtuzumab in adults with SCD who received a matched related donor HSCT to determine if the clearance of alemtuzumab affects transplant outcomes. DESIGN: PK and PD analysis of patient data from a single-center clinical trial. SETTING: Clinical research center. PATIENTS: Twenty-two adult patients with SCD who received one of two nonmyeloablative allogeneic HSCT regimens: alemtuzumab and total body irradiation (Alem-TBI) or pentostatin, cyclophosphamide, alemtuzumab, and total body irradiation (Pento-Cy-Alem-TBI). MEASUREMENTS AND MAIN RESULTS: Alemtuzumab serum concentrations, absolute lymphocyte counts, T-cell (CD3), and myeloid (CD14/15) chimerism were collected at distinct time points and analyzed. A semi-mechanistic PK population model was built to understand inter-individual differences in pharmacology. Alemtuzumab was detectable up to 28 days post-HSCT. The mean alemtuzumab level 7 days after transplant for patients on Alem-TBI was 818 ng/ml, significantly lower than the mean level of 1502 ng/ml for patients on Pento-Cy-Alem-TBI (p < 0.001), but this difference decreased as time progressed. The clearance of alemtuzumab was linear, and the half-life was longer in the Pento-Cy-Alem-TBI group (average half-life = 61.1 h) compared to the Alem-TBI group (average half-life = 44.1 h) (p < 0.001). The CD3 chimerism at 2 and 4 months after transplant positively correlated with alemtuzumab levels collected on day 14 after transplant (R(2) = 0.40 and p = 0.004 at 2 months, R(2) = 0.36 and p = 0.005 at 4 months), but this significance was lost by 6 months after HSCT. No correlation was seen between alemtuzumab levels and CD14/15 chimerism. CONCLUSION: Between 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment, suggesting more lymphodepletion may be needed to reduce graft failure in these two non-myeloablative matched related donor HSCT regimens.

Background Extracorporeal photopheresis (ECP) is an immunomodulatory cellular therapy which has been shown to induce a tolerogenic state in patients with acute and chronic graft-vs-host disease. ECOG-ACRIN explored the activity of ECP as a part of a reduced intensity conditioning regimen in two multicenter trials in patients with MDS (E1902) and lymphomas (E1402). While both studies closed before completing accrual, we report results in 23 patients (17 MDS and 6 lymphoma). Study design and methods Patients received 2 days of ECP followed by pentostatin 4 mg/m2 /day for two consecutive days, followed by 600 cGy of total body irradiation prior to stem cell infusion. Immunosuppression for aGVHD was infusional cyclosporine A or tacrolimus and methotrexate on day +1, +3, with mycophenolate mofetil starting on day 100 for chronic GVHD prophylaxis. Results All patients engrafted, with median time to neutrophil and platelet engraftment of 15-18 days and 10-18 days respectively. Grade 3 or 4 aGVHD occurred in 13% and chronic extensive GVHD in 30%. Conclusions These studies demonstrate that ECP/pentostatin/TBI is well tolerated and associated with adequate engraftment of neutrophils and platelets in patients with lymphomas and MDS.

Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, use alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with a median hematopoietic cell transplantation comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III to IV acute GVHD-free, graft-failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells, which gradually increased by day +60. The cumulative incidences of grade II to IV and grade III to IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n = 2) or with unknown underlying genetic defect (n = 3). All 6 patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.

The purine nucleoside analogues cladribine and pentostatin are highly-active first-line therapeutic treatments for hairy cell leukemia (HCL), resulting in complete response rates of 80% to 90%. However, HCL patients continue to relapse, and sooner or later, most require subsequent lines of treatment. This report presents the cases of four relapsed patients with classic HCL who were treated with vemurafenib (mostly at the low dose of 240 mg twice daily for 16 weeks) combined with rituximab after the failure of several lines of therapy including cladribine with or without rituximab and moxetumomab pasudotox. Two patients achieved minimal residual disease negative complete response after combined treatment with vemurafenib and rituximab, with a hematologic response ongoing after 38 months from the end of treatment in one patient and a relapse of cytopenias occurring after 13 months in the other patient. A third patient normalized her blood counts and this hematologic response, which was not evaluated in the bone marrow at the end of treatment, was lost after 18 months. The last patient died due to infection and multi-organ failure, too early to verify response to vemurafenib. Two patients who had relapsed after vemurafenib and rituximab derived meaningful clinical benefit from retreatment with the same agents, but eventually relapsed again and started indefinite therapy with dabrafenib and trametinib leading to normalization of the blood counts (despite heavy bone marrow infiltration in the only patient so far evaluable in that regard). The outcomes of these cases indicate that novel targeted agents and, in particular, vemurafenib, combined with rituximab, improve the prognosis of HCL patients, even those heavily pretreated with PNAs and moxetumomab pasudotox.

A 51 year-old man with hairy cell leukaemia was treated with pentostatin. While receiving the treatment, he was diagnosed with herpes retinitis in his right eye. After the last cycle of pentostatin the patient developed a mild vitritis and cystoid macular oedema. There were no signs of herpes retinitis reactivation. After excluding other possible causes of intraocular inflammation, a diagnosis of immune recovery uveitis was made. The patient was treated with 2-monthly retro-septal injections of triamcinolone, oral corticosteroids, intravitreal dexamethasone implants and, finally, pars plana vitrectomy. An immune recovery uveitis-like response is possible in HIV negative individuals. The immune reconstitution after the treatment of hairy cell leukaemia may have led to intraocular inflammation. Management of immune recovery uveitis is challenging and difficult. Pars plana vitrectomy may be necessary. Ophthalmologists should be alert to the possibility of immune recovery uveitis in HIV negative patients.

Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) may benefit from salvage chemoimmunotherapy (CIT). To explore further the use of CIT in the pre-novel agent era, ECOG-ACRIN undertook a phase 2 trial (E2903) for R/R CLL utilizing pentostatin, cyclophosphamide, and rituximab (PCR) followed by a consolidation course of alemtuzumab. This trial enrolled 102 patients with a median age of 64 years. Treatment consisted of PCR for six cycles followed by alemtuzumab for either 4 or 12 weeks depending upon the initial response to PCR. The overall response after PCR (complete remission (CR), nodular partial remission (nPR), partial remission (PR)) was 55%. Major responses (CR, or nPR) were achieved in 6%. The median overall survival (OS) and the median progression- free survival (PFS) were 28 months and 12 months respectively. The most serious non-lethal adverse events were myelosuppression, febrile neutropenia, fatigue, nausea, and hyponatremia. PCR is an effective and well-tolerated nucleoside-based regimen for heavily pretreated CLL patients with R/R disease. The addition of alemtuzumab to CLL patients with a minor response (PR) or stable disease did not result in a significant number of higher responses (CR or nPR) nor an improvement in OS.

In total, 279 patients with hairy-cell leukemia (HCL) were analyzed, with a median follow-up of 10 years. Data were collected up to June 2018. We analyzed responses to treatment, relapses, survival, and the occurrence of second malignancies during follow-up. The median age was 59 years. In total, 208 patients (75%) were treated with purine analogs (PNAs), either cladribine (159) or pentosatin (49), as the first-line therapy. After a median follow-up of 127 months, the median overall survival was 27 years, and the median relapse-free survival (RFS) was 11 years. The cumulative 10-year relapse incidence was 39%. In patients receiving second-line therapy, the median RFS was 7 years. For the second-line therapy, using the same or another PNA was equivalent. We identified 68 second malignancies in 59 patients: 49 solid cancers and 19 hematological malignancies. The 10-year cumulative incidences of cancers, solid tumors, and hematological malignancies were 15%, 11%, and 5.0%, respectively, and the standardized incidence ratios were 2.22, 1.81, and 6.67, respectively. In multivariate analysis, PNA was not a risk factor for second malignancies. HCL patients have a good long-term prognosis. PNAs are the first-line treatment. HCL patients require long-term follow-up because of their relatively increased risk of second malignancies.

T-cell large granular lymphocytic leukaemia (T-LGLL) is an incurable leukaemia characterised by clonal proliferation of abnormal cytotoxic T cells that can result in severe neutropenia, transfusion-dependent anaemia and pancytopenia requiring treatment. The most commonly used agents, methotrexate (MTX), cyclophosphamide (Cy) and cyclosporine primarily produce partial remissions (PRs), with few complete responses (CRs). We evaluated the clinical course and treatment response of 60 consecutive patients with T-LGLL to evaluate clinical outcomes and future potential treatment directions. Impaired overall survival was noted among male patients, patients with elevated lactate dehydrogenase, and those without rheumatoid arthritis. Cy was the most efficacious second-line agent, with a 70% overall response rate (ORR; three CR, four PR). All patients who failed frontline MTX responded to second-line Cy. In the relapsed or Cy-refractory setting, alemtuzumab (n = 4) and pentostatin (n = 3) had an ORR of 50% and 66%, respectively, while duvelisib induced a long-term response in one patient. In this large, retrospective analysis, our results suggest Cy is a highly effective therapy for second-line treatment in T-LGLL and should be considered a strong candidate for up-front therapy in select high-risk patients. Prospective studies evaluating pentostatin, alemtuzumab and novel agents, such as duvelisib, are needed for patients with relapsed/refractory T-LGLL.

Background Purine nucleoside analogs (PNAs) are the recommended first-line treatment for patients with hairy cell leukemia (HCL), but they are associated with adverse events (AEs). Due to a lack of real-world evidence regarding AEs that are associated with PNAs, we used commercial data to assess AE rates, AE-related health care resource utilization (HCRU), and costs among PNA-treated patients with HCL. Adults aged ≥18 years with ≥2 claims for HCL ≥30 days apart from 1 January 2006 through 31 December 2015 were included. Included patients had ≥1 claim for HCL therapy (cladribine ± rituximab or pentostatin ± rituximab [index date: first claim date]) and continuous enrollment for a ≥ 6-month baseline and ≥ 12-month follow-up period. Patient sub-cohorts were based on the occurrence of myelosuppression and opportunistic infections (OIs). Generalized linear models were used to compare HCRU and costs. Results In total, 647 PNA-treated patients were identified (mean age: 57.1 years). Myelosuppression and OI incidence were 461 and 42 per 1000 patient-years, respectively. Adjusted results indicated that those with myelosuppression had higher rates of hospitalization (47.4% vs 12.4%; P P = .011) and total costs ($57,325 vs $34,733; P = .001) as compared with those without myelosuppression. Similarly, patients with OIs had higher rates of hospitalization (53.8% vs 30.8%; P = .025) and incurred higher mean inpatient costs ($21,494 vs $11,229; P Conclusions PNA therapy is highly effective but associated with significant toxicities that increase costs; these findings indicate a need for therapies with improved toxicity profiles and better risk stratification of patients at risk of developing myelosuppression and OIs.

In a multicenter, prospective, phase II study we evaluated the safety and efficacy of pentostatin followed by donor lymphocyte infusion (DLI) in patients with low donor Tcell chimerism after allogeneic hematopoietic cell transplantation (HCT). Thirty-six patients with low donor blood CD3 chimerism were enrolled in this study. Thirty-five patients received a total of 41 DLIs after a dose of pentostatin, and 1 patient received pentostatin only. Median donor CD3 chimerism prompting the initiation of pentostatin and DLI was 28% (range, 5% to 47%). Responses (defined by increases in donor CD3 chimerism ≥10% maintained to day 56 post-DLI) were seen in 16 patients (44.4%) with a median rise in CD3 donor chimerism to 64% (range, 48% to 100%). There was a trend for better responses among 21 patients who received first treatment within 100 days after transplant (57% response rate) compared with15 patients who received first treatment more than 100 days after HCT (27% response rate, P = .07). Fourteen patients (39%) developed grades II to IV acute graft-versus-host disease (GVHD) at a median of 10 days (range, 0 to 83) after DLI. Ten patients (28%) developed extensive chronic GVHD. Seventeen patients (47%) developed new grade 4 cytopenias after DLI. There was no difference in relapse between nonresponders and responders. Twenty-eight patients (78%) died, most (n = 21) because of relapse. Five of 16 responders (31%) are alive, all disease-free, at a median of 60 months (range, 21 to 132) after DLI. Six of 20 nonresponders (30%) are alive at a median of 47 months (range, 16 to 100) after DLI, 3 in complete remission. Pentostatin and DLI had acceptable toxicity and appeared to increase low donor CD3 chimerism after HCT but had no impact on mortality.

In this study, we retrospectively analyzed the clinical outcome, treatment responses, infectious complications, and survival rates of 71 hairy cell leukemia (HCL) cases.Sixty-seven patients received a first-line treatment and 2-chlorodeoxyadenosine (cladribine-2-CdA) was administered in 31 cases, 19 patients received interferon-alpha (INF-α), splenectomy was performed in 16 cases, and rituximab was used in one.Although the highest overall response rate (ORR) was observed in patients receiving 2-CdA upfront, ORRs were comparable in the 2-CdA, INF-α, and splenectomy subgroups. Relapse rates were significantly lower in patients who received first-line 2-CdA. The progression-free survival (PFS) rate with 2-CdA was significantly higher than in patients with INF-α and splenectomy, but we found similar overall survival rates with all three upfront treatment modalities. Infections including tuberculosis were a major problem.Although purine analogues have improved the ORRs and PFS, there is still much progress to make with regard to overall survival and relapsed/refractory disease in patients with HCL.Amaç: Bu çalışmada, geriye dönük olarak 71 tüylü hücreli lösemi (SHL) olgusunu klinik sonuçlar, tedavi yanıtları, enfeksiyon komplikasyonları ve sağkalım oranları açısından analiz ettik. Gereç ve Yöntemler: Altmış yedi hasta birinci basamak tedavi almıştı ve 2-klorodeoksiadenozin (kladribin-2-CdA) 31 olguya uygulanmış, 19 hasta interferon-alfa (INF-α) almış, splenektomi 16 olguda uygulanmış ve rituksimab ise bir hastada kullanılmıştı. Bulgular: En yüksek toplam yanıt oranı (TYO) birinci basamak 2-CdA alan hastalarda görülmüş olsa da, TYO’lar 2-CdA, INF-α ve splenektomi alt gruplarında benzerdi. Nüks oranları birinci basamak 2-CdA alan hastalarda anlamlı olarak daha azdı. Progresyonsuz sağkalım (PS) oranı 2-CdA alanlarda INF-α ve splenektomi hastalarına göre anlamlı olarak daha yüksek olmakla birlikte, her üç birinci basamak tedavi yaklaşımı ile toplam sağkalım (TS) oranları benzer olarak bulundu. Tüberkülozun da dahil olduğu enfeksiyonlar önemli bir problemdi. Sonuç: Her ne kadar pürin analogları TYO ve PS’yi iyileştirmiş olsa da, SHL hastalarında TS ve nüks/dirençli hastalık açısından daha yapılması gereken çok şey vardır. Anahtar Sözcükler: Kladribin, Tüylü hücreli lösemi, İnterferon, Splenektomi.

Hairy cell leukemia (HCL) is a rare hematologic malignancy with high response rates and long progression-free survival (PFS) after treatment with purine nucleoside analogs (PNAs; Pentostatin/Cladribine). However, treatment is not curative, and subsequent treatment at relapse is often required. Rechallenge with a purine analog is commonly implemented despite limited data regarding the efficacy of this approach. We retrospectively analyzed 61 consecutive patients with HCL diagnosed between 1995 and 2013 at Cleveland Clinic. Median follow-up was 72 months (3-193). Cladribine as first-line therapy was administered to 59 patients (97%). Overall response rate (ORR) was 97%, with 78% of patients achieving complete remission (CR). PFS after response was significantly improved for patients who achieved CR compared with those with a partial remission (PR) (5-year PFS 71% vs. 39%, respectively [P = .004]). Of the 19 patients who relapsed, 12 received PNAs as second-line treatment with an ORR (83%) comparable to what these patients had with first-line treatment (ORR 92%). Overall survival of all 61 patients was excellent and superior to that of age-, sex-, and race-matched controls from the general population, possibly due to selection bias. In an analysis of a larger cohort of unselected patients in the Surveillance, Epidemiology, and End Results (SEER) database, we found that mortality rates for patients with HCL were similar to those of the general population approximately 5 years after diagnosis. These data confirm the excellent prognosis for patients with HCL after first- and second-line PNA therapy.

Background T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive disease. In this study, we report our experience from 119 patients with T-PLL. Patients and methods We reviewed the clinico-pathologic records of 119 consecutive patients with T-PLL, who presented to our institution between 1990 and 2016. Results One hundred and nineteen patients with T-PLL were analysed. Complex karyotype and aberrations in chromosome 14 were seen in 65% and 52% patients, respectively. Seventy-five patients (63%) were previously untreated and 43 (37%) were initially treated outside our institution. Sixty-three previously untreated patients (84%) received frontline therapies. Overall, 95 patients (80%) have died. Median overall survival (OS) from diagnosis was 19 months [95% confidence interval (CI) 16-26 months]. Using recursive partitioning (RP), we found that patients with hemoglobin

Isolated pleural metastasis with pleural effusion is a rare occurrence in malignant melanoma. We report an unusual case of a patient with chronic lymphocytic leukemia (CLL) and recurrent pleural effusions. The pleural fluid cytology and immunohistochemistry profile were consistent with the diagnosis of CLL. However, chemotherapy with pentostatin, cyclophosphamide, and rituximab did not result in any meaningful clinical response. A video-assisted thoracoscopic surgery and biopsy of the affected nodular parietal layer of the pleura were consistent with malignant melanoma. Our case underlines the importance of having a suspicion for secondary causes of effusion in patients with CLL. We briefly discuss the mechanisms of an increased incidence of secondary cancers in CLL and the diagnosis of isolated pleural metastases in malignant melanoma.

Introduction: Cladribine and pentostatin are the drugs of choice in the treatment of hairy cell leukemia (HCL). Recently, immunotoxin moxetumomab pasudotox has been introduced to improve the prognosis in relapsed and refractory HCL. Areas covered: This review discusses the mechanism of action, safety, and efficacy of moxetumomab pasudotox in HCL patients. A literature review of the MEDLINE database for articles in English concerning immunotoxins, moxetumomab pasudotox, and hairy cell leukemia was conducted via PubMed. Publications from 2000 through December 2018 were scrutinized. The search terms used were immunotoxins and moxetumomab pasudotox in conjunction with hairy cell leukemia. Conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association and American Society of Clinical Oncology were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. Results/conclusion: Moxetumomab pasudotox, a novel recombinant anti-CD22 immunotoxin, was well tolerated and active in the previous phase 1 and 3 studies in patients with HCL. The drug has been approved in 2018 by the FDA for the treatment of patients with relapsed/refractory HCL who had at least two prior systemic therapies including at least one purine nucleoside analog. Expert opinion: The use of moxetumomab pasudotox is a promising new strategy for the treatment of HCL.

Objective: To review the literature for the treatment of classical and variant hairy cell leukemia (HCL, HCLv), evaluating efficacy, safety, and supportive care involved in the use of purine analogues (PAs), interferon, BRAF inhibitors, monoclonal antibodies, Bruton’s tyrosine kinase inhibitors, and new immunotoxin, moxetumomab pasudotox-tdfk (MPT). An electronic literature search of PubMed (January 1958 to January 2019) was conducted in PubMed using the MESH terms hairy cell leukemia, hairy cell leukemia variant, cladribine, pentostatin, rituximab, interferon, vemurafenib, moxetumomab pasudotox. Study Selection and Data Extraction: Studies written in the English language were considered for this article. The significance of each article was determined by authors independently. Data Synthesis: HCL and HCLv are rare B-cell lymphoproliferative disorders, each with distinct biologies. Symptoms are characterized by pancytopenia and splenomegaly. Initial treatments for HCL were suboptimal, leading to minimal and transient remissions. PAs significantly improved outcomes, inducing remission in most patients. However, those with purine-resistant disease were left with a dearth of options, leading to implementation of vemurafenib for BRAF V600 mutated disease and chemoimmunotherapy with rituximab. Despite these advances, some HCL and a majority of HCLv patients experience relapse. Newer targeted agents offer promise for relapsed and refractory patients, including the recently approved MPT. Relevance to Patient Care and Clinical Practice: This review provides a comprehensive update on the pharmacological management of HCL and HCLv for clinicians who encounter patients with this rare disease. Conclusion: HCL and HCLv are uncommon lymphoid neoplasms that lead to a characteristic constellation of symptoms. The emergence of PAs and novel targeted agents have improved the likelihood and durability of responses for these patients.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive postthymic T-cell neoplasm with an associated survival time of 1 year when left untreated. Current standard of care for T-PLL is with alemtuzumab, followed by allogeneic or autologous stem cell transplant. Little is found in the literature about alternative donor transplantation in T-PLL. Here, we present the case of a patient treated with double umbilical cord blood transplantation, which resulted in initial complete remission. An unusual outcome of this case is that coengraftment of both cords was established. After 16 months, the patient had relapse of the disease, unfortunately, prompting treatment with alemtuzumab and pentostatin, which resulted in remission once again. Here, we report a unique phenomenon whereby single-cord dominance occurred after treatment with these agents, suggesting that anti-T-cell therapy after transplant may help achieve single-unit dominance. A second relapse of the disease occurred six months thereafter, ultimately resulting in the patient’s death, highlighting the aggressive nature of this disease.

Most patients with treatment naïve classical hairy cell leukemia (cHCL) have durable responses with purine nucleoside analogues. In contrast, options are limited for cHCL patients with co-morbidities, purine analogue intolerance, or resistant disease. We report the utility of targeted therapy for nine cHCL patients presenting with treatment naïve cHCL and severe neutropenia and infection (n = 3), purine analogue intolerance (n = 2), or purine analogue resistant disease (n = 4). BRAF inhibitor vemurafenib was started at 240-480 mg twice daily (planned 90-day treatment) and combined with rituximab in seven patients. Therapy was tolerable with no severe adverse events. All patients responded with rapid blood count recovery (median time 1.52 months, range 0.43-4.33). Median progression free and overall survival was not reached at a median follow up of 18.1 months (range 3.2-68.9). These data suggest targeted therapy could be an option for patients unable to be treated with purine analogues.

// Neil E. Kay 1 , Paolo Strati 1 , Betsy R. LaPlant 1 , Jose F. Leis 2 , Daniel Nikcevich 3 , Timothy G. Call 1 , Adam M. Pettinger 1 , Connie E. Lesnick 1 , Curtis A. Hanson 1 and Tait D. Shanafelt 1 1 Mayo Clinic College of Medicine, Rochester, MN, USA 2 Mayo Clinic College of Medicine, Scottsdale, AZ, USA 3 Essentia Health’s East Region, Duluth, MN, USA Correspondence to: Neil E. Kay, email: // Keywords : CLL, chemoimmunotherapy, bevacizumab Received : October 15, 2016 Accepted : November 09, 2016 Published : November 16, 2016 Abstract Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF) with in vitro pro-apoptotic and antiangiogenic effects on chronic lymphocytic leukemia (CLL) cells. As monotherapy in patients with CLL, it has no clinical activity. Here we report the results of an open-label, randomized phase II trial comparing the combination of pentostatin, cyclophosphamide and rituximab (PCR) either without or with bevacizumab (PCR-B) in previously untreated CLL patients. A total of 65 evaluable patients were enrolled, 32 receiving PCR and 33 PCR-B. A higher rate of grade 3-4 cardiovascular toxicity was observed with PCR-B (33% vs . 3%, p < 0.003). Patients treated with PCR-B had a trend for a higher complete remission (CR) rate (54.5% vs 31.3%; p = 0.08), longer progression-free survival (PFS)( p = 0.06) and treatment-free survival (TFS)( p = 0.09). No differences in PFS and TFS by IGHV mutational status were observed with the addition of bevacizumab. A significant post-treatment increase in VEGF levels was observed in the PCR-B arm (29.77 to 57.05 pg/mL); in the PCR-B arm, lower baseline CCL-3 levels were significantly associated with achievement of CR ( p = 0.01). In conclusion, the addition of bevacizumab to chemoimmunotherapy in CLL is generally well-tolerated and appears to prolong PFS and TFS.

Summary Background Although several consolidation strategies to prolong treatment-free survival (TFS) in chronic lymphocytic leukaemia have been investigated, most have proven either ineffective or toxic. Ofatumumab is a human type I anti-CD20 antibody approved by the US Food and Drug Administration as maintenance treatment of patients with recurrent or progressive chronic lymphocytic leukaemia who are in complete or partial response after at least two lines of treatment; higher efficacy might be observed if used as consolidation strategy than without consolidation in previously untreated patients. Methods We recruited patients with previously untreated progressive chronic lymphocytic leukaemia who had an Eastern Cooperative Oncology Group performance status of 0–2 and adequate renal and hepatic function from centres in the USA. Patients with recent myocardial infarction; class III or IV heart failure; uncontrolled, HIV, or active hepatitis B or C infection; or active haemolytic anaemia were excluded. In the first arm of this study, which has been previously reported, patients were treated with six cycles of induction with pentostatin (2 mg/m 2 on day 1), cyclophosphamide (600 mg/m 2 on day 1), and ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg/m 2 on day 2; cycles 2–6: 1000 mg/m 2 on day 1) given intravenously every 21 days. Here were report the second arm, where patients received the same regimen as the first arm, with the addition of six cycles of consolidation with ofatumumab (1000 mg once every 4 weeks), also given intravenously. The primary endpoint was TFS at 18 months, assessed in those who began consolidation. We estimated the distribution of TFS using the Kaplan-Meier method, assessing between-group differences with log-rank statistics. The phase 2 trial, which is completed, is registered at ClinicalTrials.gov, number NCT01024010. Findings Between Sept 21, 2011, and Nov 7, 2012, 34 patients were recruited to this second arm of the trial. Among the 31 (91%) patients who completed induction treatment and started consolidation, 26 (84%) completed the planned six cycles of ofatumumab consolidation. TFS at 18 months was 94·1% (95% CI 78·5–98·5). Grade 3 or worse adverse events deemed at least possibly related to treatment were neutropenia (14 [41%] patients), infection (2 [6%]), and one (3%) each with anaemia, haemolysis, fatigue, and a neurological, metabolic, respiratory, and vascular complication. Interpretation Ofatumumab-based consolidation appears to be a well tolerated and effective consolidation strategy in patients with chronic lymphocytic leukaemia, which could improve survival. Funding GlaxoSmithKline.

The monoclonal gammopathies of renal significance (MGRS) are a group of disorders characterized by monoclonal Ig deposition in the kidney, but are not associated with systemic lymphoma or overt multiple myeloma. The prevailing hypothesis is that the pathogenic paraproteins in MGRS are produced by underlying B cell or plasma cell clones. However, in the MGRS literature, the yield of detecting a clone has been variable, and progression to ESRD is common. Here, we present an “onco-nephrologic” approach to the MGRS disorders by highlighting recent advances in lymphoma and multiple myeloma that can be used in the evaluation and management of these patients.

Introduction B-cell prolymphocytic leukemia (B-PLL) is a rare, aggressive leukemia distinct from chronic lymphocytic leukemia, with median survival of only 3 years. B-PLL is resistant to most chemotherapy and newer targeted therapies such as alemtuzumab and thalidomide. Phenylethyl isothiocyanate (PEITC) is a natural compound from horseradish with evidence for therapeutic potential in multiple leukemia types. Case presentation Here we present a case report of a 53-year-old man whose chronic lymphocytic leukemia transformed to end-stage B-PLL, disqualifying him for allogenic stem cell transplantation. He was treated with PEITC followed by salvage R-CHOP (Rituximab, Cyclophosphamide, Hydroxydaunorubicin [doxorubicin hydrochloride], Oncovin [vincristine sulfate], Prednisone or Prednisolone) chemotherapy, which led to normalized white blood cell count and disease stabilization that requalified him for allogenic peripheral stem-cell transplant therapy. We conducted a systematic review to analyze and interpret the potential contribution of PEITC to his unexpectedly favorable R-CHOP response. Following sequential 8 weeks of PEITC/pentostatin and 6 cycles of R-CHOP, the patient received allogenic peripheral blood stem cell transplant on an outpatient basis and remains well at the time of this publication, with no evidence of CD20+ small B-cells. Discussion Given the limited data for R-CHOP in B-PLL, this patient's recovery suggests presensitization of B-PLL cells toward R-CHOP, potentially justifying further investigation.

A 65-year-old woman presented with easy bruising, left upper quadrant pain, decreased appetite, and weight loss. She had splenomegaly and lymphocytosis (lymphocyte count of 11.6 × 109/l), with remarkably abnormal appearing morphology. Her hemoglobin and platelet counts were normal. Peripheral blood flow cytometry revealed a monoclonal B-cell population expressing CD11c, CD25, CD19, CD20, and CD103. An initial diagnosis of hairy cell leukemia (HCL) was made, and the patient was treated with a standard 5-day course of cladribine. However, her lymphocytosis improved transiently, with a relapse 4 months later. There was no improvement in her splenomegaly. An HCL variant (HCL-v) was considered based on her resistance to treatment with a purine nucleoside analog. A subsequent splenectomy improved symptoms. Two years after, the patient suffered a relapse and underwent 6 cycles of CHOP-R (cyclophosphamide, hydroxydaunomycin, oncovin, prednisone, and rituximab), achieving partial remission. While under observation, she progressed with lymphocytosis 6 months later and was treated with pentostatin. There was no significant improvement in her disease, and she died 8 weeks following treatment initiation. HCL-v is a clinically more aggressive mature B-cell lymphoma than HCL with worse splenomegaly, higher lymphocyte counts, and resistance to typical HCL therapy with purine nucleoside analogs. Early recognition of HCL-v in the history, physical examination, and investigations with morphology and flow cytometry is key to patient management. Further, as in our case of HCL-v, cell morphology can be distinctly atypical, with large nucleoli and extremely convoluted nuclei. The distinction between HCL and HCL-v is important as HCL-v patients require more aggressive therapy and closer follow-up.

Introduction T-NHL are associated with an aggressive clinical course and poor outcomes. The role of PET-CT at the time of SCT (pre-SCT), BM biopsy, and peripheral blood (PB) flow cytometry have not been well investigated. We retrospectively analyzed 83 pts with T-NHL undergoing auto or allo SCT to determine the predictive value of pre-SCT PET-CT scan, BM and PB flow for relapse-free survival (RFS) and OS. Methods PET CR was defined as the absence of any radiographic dz by PET-CT (5-pt score). Overall CR was defined as negative PET, BM and PB flow. Pre-SCT variables were assessed for their effects on RFS and OS: age, number of previous lines of therapy, CIBMTR dz risk, pre-SCT BM, pre-SCT PB flow, and pre-SCT PET-CT. Results Of 83 pts studied, 49 were autoSCT and 34 were alloSCT. Six pts who underwent alloSCT had received a prior autoSCT. Diagnosis was PTCL NOS 34, AITL 23, CTCL/Sezary syndrome 11, nasal NK-T 6, EATL 3, SPTCL 2, hepatosplenic 1, ALK-ALCL 1, HTLV-2 ATL 1, T-lymphoblastic 1. The majority of pts with AITL (16/23) underwent autoSCT upfront. Conditioning for autoSCT was BEAM. Conditioning for alloSCT was Pentostatin/TBI in all but 6 SCT. Median lines of therapy prior to SCT were 1 for auto and 4 (r 2-13) for alloSCT. Median age at SCT was 60 (r 20-75). A total of 6 out of 49 (12%) autoSCT and 8 out of 34 (24%) alloSCT had positive PET-CT (score 4-5) at the time of SCT. BM was positive in 8 out of 49 (16%) at the time of autoSCT and 7 out of 34 (21%) at the time of alloSCT. PB flow was positive in 9 out of 49 (18%) at the time of auto SCT and 6 out of 34 (12%) at the time of alloSCT. CIBMTR dz index was low in 57(69%), intermediate in 15(18%), and high in 11 (13%) of 83 SCT. The majority of allo-SCT were intermediate-high risk. The median follow-up 56 months (r 6 - 122). Twenty (24%) pts had expired. Univariate analysis of pre-autoSCT variables did not reveal statistically significant (SS) results for BM or PET positivity. Univariate analysis of pre-alloSCT variables identified positive BM and positive PET/CT scan as being SS. There was a SS lower incidence of relapse, longer RFS and OS in alloSCT pts with either negative pre-SCT PET-CT scan or negative pre-SCT BM. Other pre-SCT variables tested were not SS. In multivariate analysis, pre-alloSCT PET-CT alone retained SS. Pre-alloSCT PET-CT scan was a strong predictor of 2-yr RFS and 2-yr OS. Conclusion This data indicates that in heavily pretreated pts with T- NHL undergoing alloSCT, a negative pre-SCT PET-CT is a statistically significant predictor of long-term RFS and OS regardless of dz risk and number of lines of therapy. Due to the small number of autoSCT with positive PET-CT scans, BM biopsy, or PB flow at the time of SCT, no association between the above-mentioned variables and relapse was identified. Further studies with larger numbers of pts are warranted to determine the role of pre-autoSCT PET-CT, BM and PB flow as prognostic factors in T-NHL.

In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well-tolerated in previously untreated patients with advanced-stage, indolent non-Hodgkin lymphoma (iNHL). After a median patient follow-up of more than 108 months, we performed an intent-to-treat analysis of our 83 participants. Progression-free survival (PFS) rates at 108 months for follicular lymphoma (FL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL) were 71%, 67% and 15%, respectively, and were affected by clinicopathological characteristics. Ten-year PFS rates for those with beta-2-microglobulin levels

Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab. Outpatients received low-dose conditioning therapy with cyclophosphamide (600 mg/m(2)), followed by escalating doses of 3 × 10(6), 1 × 10(7), or 3 × 10(7) 19-28z CAR T cells/kg. An objective response was observed in 3 of 8 patients (38%), with a clinically complete response lasting more than 28 months observed in two patients. Self-limited fevers were observed post-CAR T cell infusion in 4 patients, contemporaneous with elevations in interleukin-6 (IL-6), IL-10, IL-2, and TGF-α. None developed severe cytokine release syndrome or neurotoxicity. CAR T cells were detectable post-infusion in 4 patients, with a longest observed persistence of 48 days by qPCR. Further strategies to enhance CAR T cell efficacy in CLL are under investigation.

We report outcomes of 60 patients with steroid-refractory (SR)-aGVHD treated with pentostatin. Almost half (47%) of patients had grade 4 GVHD-22% had stage 3-4 liver GVHD and 51% had stage 3-4 lower gastrointestinal tract (LGI) GVHD. Patients received a median of 3 courses (range, 1-9) of pentostatin. Day 28 overall response rate (ORR) was 33% (n = 20) (complete response 18% (n = 11), partial response 15% (n = 9)). Non-relapse mortality was 72% (95% confidence interval (CI) 61-84%) and overall survival (OS) was 21% (95% CI 12-32%) at 18 months. On univariate analysis, age >60 years (HR 1.9, 95% CI 1.01-3.7, p = 0.045) and presence of liver GVHD (HR 1.9, 95% CI 1.9, 95% CI 1.5-3.3, p = 0.03) were significant predictors of poor OS while patients with LGI GVHD had superior OS than those without (HR 0.4, 95% CI 0.2-0.8, p = 0.01). On stratified analysis, patients

7 regimens of pentostatin based chemoimmunotherapy (CIT) for progressive previously untreated CLL primarily with long term follow-up to update both efficacy and toxicity.Prognostic markers including assessment of IGVH and FISH status were done on all. Response rates and 95% binomial confidence intervals were calculated for each regimen and in the combined cohort. Overall survival and treatment-free survival were evaluated using Kaplan-Meier methods.The initial CIT trial was pentostatin (2 mgs/m2), cyclophosphamide (600 mg/m2) and rituximab (PCR) but subsequent P based CIT trials with modifications in subsequent trials. The cohort (n = 288) included 52% with unmutated IGVH status and del17p (4.5%) and del11q (14.9%). Toxicity profiles were primarily hematologic and no patient has developed MDS or AML after a median follow-up of 6.4 years. The overall response rate across all trials was found to be over 90% with a 41% complete response rate. We validated that the CLL IPI model segregates progressive CLL patients into 4 risk groups associated with OS and TFS.The high overall and complete response levels in favorable genetic risk CLL along with favorable toxicity profiles provide rationale for consideration of a PC based strategy for previously untreated progressive CLL.

Introduction Chronic graft-versus-host disease (cGvHD) is a complication following allogeneic hematopoietic stem-cell transplants (HSCT) occurring when immune cells transplanted from a non-identical donor (i.e., the graft) recognize the transplant recipient (i.e., the host) as foreign. Systemic therapy for ≥1 year is required for patients who meet criteria for moderate-to-severe cGvHD using NIH consensus criteria. This study assessed continuation of secondary systemic treatments (SSTs) in cGvHD patients in the United States (US). Methods A retrospective analysis was conducted using the Truven Health MarketScan® claims databases (2009–2016). Adult cGvHD patients receiving SST with continuous enrollment (3 months before first cGvHD diagnosis [baseline] and 6 months after SST initiation) were eligible. SST was defined by Flowers et al (2015)1 and included extracorporeal photopheresis (ECP), rituximab, imatinib, pentostatin, or mTOR inhibitors, continuous SST use was defined as ≥180 days of therapy (yes vs. no) and treatment persistence was evaluated using a 45-day gap. Patient demographics, clinical characteristics, health care resource use, and costs were summarized by SST continuation status. A multivariate regression model assessed factors associated with SST continuation. Results The study included 464 patients with ≥2 SST claims (mean age 49.7 years; 61.0% male). The most frequently used SSTs (not mutually exclusive) were mTOR inhibitors 293 (63.1%), ECP 210 (45.3%) and imatinib 51 (11.0%). The mean (median) treatment duration was 12.9 (8.3), 11.1 (8.0), and 12.5 (7.5) months for mTOR inhibitors, ECP and imatinib, respectively. A total of 172 (37.1%) patients were SST continuers and 292 (62.9%) were discontinuers. Baseline demographic and clinical characteristics were similar between SST continuers and discontinuers. The mean time from cGvHD diagnosis to initiation of SST was shorter for discontinuers vs. continuers (5.0 vs 6.2 months, (P =.118). Compared with SST continuers, SST discontinuers had higher average monthly hospital costs post-SST initiation ($15,848 vs. $6,286, P =0.047). The proportion of SST continuers was the highest (52.9%) among ECP patients, followed by patients receiving imatinib (33.3%) and mTOR inhibitors (21.5%). Regression results revealed that ECP patients were >3 times more likely to be SST continuers (adjusted OR: 3.18, P Conclusions Approximately 2 in 5 cGvHD patients were SST continuers with median treatment duration of 15 months. SST continuers had lower monthly hospitalization costs than discontinuers during the follow-up period, indicating a potential cost benefit for treatment continuity. Multivariate regression analysis indicated that ECP treatment is significantly associated with SST continuation. These findings should be interpreted with caution as the reasons for discontinuation are unknown.

Hairy cell leukemia patients are at increased risk for second malignancies, including both solid and lymphoid neoplasms. Along with other factors, multiple immune defects present in hairy cell leukemia likely contribute to subsequent carcinogenesis. We report herein a case of synchronous high-grade gastric and ampullary adenocarcinomas in a patient with a history of hairy cell leukemia treated eight years prior with pentostatin. We include a review of immune alterations induced by both hairy cell leukemia and its therapies, and link them with the occurrence of second cancers in these patients.

Background A limited evidence exists regarding comparisons of clinical effectiveness of available therapies for first-line treatment of chronic lymphocytic leukemia (CLL). Methods We compared available therapies for treatment-naive, symptomatic CLL regarding progression free survival (PFS) and overall survival (OS) in all the identified random control trials and in subgroups composed of younger/fit and older/unfit patients, using a Bayesian network meta-analysis. Results In younger/fit patients we obtained median of projected mean PFS of: 19, 26, 31, 43, 51 and 75 months for chlorambucil, fludarabine, alemtuzumab, fludarabine with cyclophosphamide (FC), bendamustine and fludarabine with cyclophosphamide and rituximab (FCR), respectively. We noted median OS of: 59, 66, 66, 70 months for FC, chlorambucil, FCR and fludarabine, respectively. In older/unfit patients we noted PFS of: 16, 17, 24, 30, 60 months for chlorambucil, fludarabine and chlorambucil with ofatumumab (OClb) or rituximab (RClb) or obinutuzumab (GClb), respectively. We obtained median OS of: 44, 58, 59 and 90 months for fludarabine, RClb, chlorambucil and GClb, respectively. Conclusions Our results suggest that: (1) FCR has higher potential of preventing CLL progression in younger/fit patients over four therapy options, which were subject of previous meta-analysis but also over bendamustine; (2) in these patients FCR does not entail prolonging of OS in comparison with chlorambucil and it is outperformed by fludarabine; (3) in older/unfit patients GClb demonstrates longer projected PFS than all assessed comparators; (4) in this group GClb has also the highest potential of increasing OS.

Introduction Pentostatin (2′-deoxycoformycin) and cladribine (2-chlorodeoxyadenosine) are adenosine analogues widely used to treat lymphoid malignancies, mainly hairy cell leukemia (HCL). Oral or parenteral adenosine analogues have been also used as immunomodulatory agents in multiple sclerosis and in acute graft-versus-host disease. Case Report Here, we report the case of a 43-year-old patient with a history of extensive psoriasis who later developed HCL. Results The patient had achieved complete remission of both psoriasis and HCL after receiving intravenous infusions of pentostatin. It is worth noting that cladribine has already been reported to treat plaque psoriasis lesions in two patients with HCL and in a third patient with gastric marginal zone B cell lymphoma [1]. Conclusion We believe that adenosine analogues constitute a promising therapeutic option for moderate to severe psoriasis, especially for severe and refractory psoriasis, as well as for patients with adjacent lymphoid malignancies.

Patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL) display a dismal prognosis and their therapy represents an unmet medical need, as the best treatment strategy is yet to be determined. Exciting data on novel targeted agents are now emerging from recently concluded and ongoing clinical trials in patients with relapsed and refractory CTCL. Three FDA approved compounds are used as single agents including the oral retinoid bexarotene and histone deacetylase inhibitors romidepsin and vorinostat. Brentuximab vedotin, an anti-CD30 drug-conjugated monoclonal antibody, has received from European Commission the orphan designation but has not been approved by EMA yet. Several other molecules have demonstrated their activity in the same context and combination strategies are being explored. Participation in a well designed clinical trial is encouraged, as the introduction of novel agents will continue to expand the therapeutics options available in the management of CTCL.

In this multicenter retrospective analysis, we aimed to present clinical, laboratory and treatment results of 94 patients with Hairy cell leukemia diagnosed in 13 centers between 1990 and 2014. Sixty-six of the patients were males and 28 were females, with a median age of 55. Splenomegaly was present in 93.5% of cases at diagnosis. The laboratory findings that came into prominence were pancytopenia with grade 3 bone marrow fibrosis. Most of the patients with an indication for treatment were treated with cladribine as first-line treatment. Total and complete response of cladribine was 97.3% and 80.7%. The relapse rate after cladribine was 16.6%, and treatment related mortality was 2.5%. Most preferred therapy (95%) was again cladribine at second-line, and third line with CR rate of 68.4% and 66.6%, respectively. The 28-month median OS was 91.7% in all patients and 25-month median OS 96% for patients who were given cladribine as first-line therapy. In conclusion, the first multicenter retrospective Turkish study where patients with HCL were followed up for a long period has revealed demographic characteristics of patients with HCL, and confirmed that cladribine treatment might be safe and effective in a relatively large series of the Turkish study population.

Extracorporeal photopheresis (ECP) and the purine analog pentostatin exert potent immunomodulatory effects. We evaluated the use of these treatment modalities to prevent GVHD in a canine model of unrelated dog leukocyte antigen mismatched hematopoietic cell transplantation (HCT), after conditioning with 920 cGy total body irradiation (TBI). We have shown previously in this model that 36/40 dogs given methotrexate (MTX) alone as postgrafting immunosuppression engrafted and that 25 of 40 dogs had severe GVHD and median survival of 21 days. In the current study, 9 dogs received conditioning with 920 cGy TBI and postgrafting MTX either with ECP on days −2 to −1 alone (n=5) or ECP on days −6 and −5 combined with 2 doses of pentostatin (days −4 to −3) (n=4). Seven of 9 dogs achieved engraftment. Six dogs developed severe acute GVHD (4 in the group with ECP alone and 2 with Pentostatin and ECP). We failed to demonstrate a positive impact of ECP and pentostatin for the prevention of GVHD compared to historical control dogs.

Background: Hairy cell leukemia (HCL) is an indolent mature B-cell disorder that comprises ~2% of all leukemias. Purine nucleoside analogues (PNA) such as cladribine and pentostatin remain the standard initial treatment with high response rate, however frequent late relapses occur. The addition of rituximab (R) has shown efficacy as a single agent and in combination in the first- and second-line settings . Recent data suggests that the addition of R to PNA increased the minimal residual disease (MRD) negative (neg) and duration of response (DOR) when compared to PNA alone. In this study, we examined the impact of rituximab (R) in the long term outcomes of HCL from a single institution experience. Methods: An IRB-approved retrospective analysis was performed including patients with HCL or HCL-variant who were seen at Moffitt Cancer Center between 1/2000 and 2/ 2019. Primary endpoints were overall (OS) and progression-free survival (PFS). Secondary endpoints included overall response rate (ORR). Complete Remission (CR) was determined based off of accepted criteria of Hgb > 11gr/dL, platelets > 100,000/µL and ANC > 1500/µL. Statistical comparisons and survival analyses were performed using SPSSTM Statistics and GraphPad PrismTM. Results: We identified 124 cases with available treatment data and follow up (82 HCL, 15 CD25-negative HCLv). The median follow-up was 72 months. The median age was 57 years (27 - 89+). The 5 and 10 year OS was 97% and 91%, respectively, with 2 deaths reported secondary to HCL or complications from HCL. The median PFS for all patients receiving first-line therapy was 92 months. Clinical risk factors present at diagnosis that were independently associated with worse PFS after first-line therapy were weight loss (HR 2.27, p = 0.057), recurrent infections (HR 2.50, p=0.009) and splenomegaly (HR 1.87, p=0.047),, hemoglobin less than 11 gr/dL (HR 3.12, p=0.016), and negative CD25 (HR 2.14, p=0.055). In multivariate analyses, negative CD25, recurrent infections and Hgb < 11 gr/dL were associated with worse PFS after first line therapy (p = 0.002). Most patients received PNA alone or PNA+R (96 and 18, respectively) as first line with a higher CR rate in the PNA+R group (100% vs 71%) and a higher median PFS for [not reached (NR) and 82 months, respectively, p = 0.165] with 2 relapses in the PNA+R group (both at 30 months). In the 2nd line setting, PNA+R (n = 11) was also associated with a higher CR rate than PNA alone (n = 22, 82% vs 64%) with only 1 relapse in the PNA+R group at 97 months. The median PFS for 2nd line PNA+R vs 2-CdA was 97 and 43 months, respectively (p = 0.253). Conclusions: In this study, we report a large, retrospective, single-institution dataset of HCL and HCLv patients with long-term follow-up. The addition of R may improve the PFS in patients with HCL in the first and 2nd -line settings however a longer follow up is needed. A recently described prospective randomized trial in the use of concomitant rituximab plus PNA has reported a higher MRD free CR in comparison with PNA alone but not PFS yet. Disclosures Chavez: Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Pinilla Ibarz:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy; TG Therapeutics: Consultancy; Bayer: Speakers Bureau; Sanofi: Speakers Bureau.

Introduction: Hairy-cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder with a favorable outcome thanks to treatment with purine analogues (PNA) like cladribine and pentostatin. Here, we updated the French national retrospective cohort of HCL after 10 years of follow-up, in order to evaluate the risk of second cancers in these patients. Methods: Data were collected up to June 2018 through a questionnaire sent to the members of the Société Française d'Hématologie, and centralized in the cohort database. We described the second malignancies observed during the follow-up, distinguishing second 'solid' cancers from second hematological malignancies. Then, using a Fine and Gray model, we performed a multivariate analysis in order to identify second cancer risk factors. Finally, to evaluate the excess of cancers in our cohort in comparison with the French general population, we calculated the standardized incidence ratio (SIR). Results: 279 patients (pts) from 19 centers were included in our retrospective cohort. The median age was 59 years old (range 29-88). 21% had an infectious disease at diagnosis, 23% had a familial history of cancer and 11% a personal history of cancer before HCL diagnosis. The median number of lines of treatments was 1 (0-7). PNA (cladribine or pentostatin) were the first therapeutic choice in frontline (75% of pts) and at relapse (69%). With a median follow-up of 127 months (2-413), the median overall survival for the overall study population was 328 months (95% CI 299-357) and the median relapse-free survival (RFS) was 136 months (95% CI 109-163). Pts treated with cladribine or pentostatin in first line had a statistically significant better RFS than pts treated with 'other' treatments (log rank test, p < 0.001). The 10-year cumulative incidence of relapse was 39% (95% CI 33-46). Pts who received treatments other than PNA in first line had a higher risk of relapse (Gray's test, p < 0.001). For pts receiving PNA in first and second lines, there was no difference in outcomes between those who switched PNA and those who did not. In this cohort, we observed 68 second malignancies during the follow-up: 49 solid cancers (most prevalent: prostate and non-melanoma skin cancers) and 19 hematological malignancies (most prevalent: monoclonal gammopathy of undetermined significance (MGUS) and myelodysplastic syndromes (MDS)). The median onset of second cancer, second solid cancer and second hematological malignancy from HCL diagnosis was 81 months, 99 months and 78 months, respectively. The median age at diagnosis of cancer, solid cancer and hematological malignancy was 70, 69 and 77 years old, respectively. Considering death as a competing risk, the 10-year cumulative incidence of cancer, solid cancer and hematological malignancy was 15% (95% CI 11-19), 11% (95% CI 7.2-15), and 5.0% (95% CI 2.8-8.2), respectively. In multivariate analyses, IFN treatment was associated with a decreased risk for all cancers (Fine and Gray regression model, subdistribution Hazard Ratio (sdHR) 0.53 (95% CI 0.29-0.97); p = 0.038), a familial history of cancer was a risk factor for solid cancers (sdHR 2.12 (95% CI 1.15-3.91); p = 0.017), a personal history of cancer was a risk factor for hematological malignancies (sdHR 3.47 (95% CI 1.14-10.55); p = 0.028). Even after excluding non-melanoma skin cancers and MGUS, there was an excess of cancers (SIR = 2.22), solid cancers (SIR = 1.81) and hematological malignancies (SIR = 6.67). Conclusions: In this updated real-world retrospective cohort with a long follow-up and most pts treated with PNA, we highlighted the importance and the excess of second cancers in HCL patients, in particular hematological malignancies. Figure Disclosures Paillassa: Janssen: Other: Bibliography board with young hematologists. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Hermine:AB Science: Membership on an entity's Board of Directors or advisory committees. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau. Troussard:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Research Support; Sysmex: Other: Research Support.

Background Hairy cell leukemia (HCL) is a rare and indolent lymphoproliferative disorder. Frontline treatment with a single course of the purine nucleoside analog (PNA) cladribine (or pentostatin) produces a high rate of complete remission (CR) with prolonged durations. At the time of relapse, treatment guidelines recommend re-treatment with a PNA alone or in combination with rituximab (R) but practice patterns vary and data supporting each approach are limited. Methods We conducted a multi-site outcomes analysis of patients treated for HCL between 1995-2018 at 5 US medical centers. All patients were treated with frontline PNA and subsequently required treatment for relapsed/refractory (r/r) disease with a PNA alone (PNA) or a PNA with R (PNA+R). Decision to use R was made by the treating physician. Baseline characteristics were compared between treatment cohorts using Fisher's exact and Wilcoxon rank sum tests. Overall survival (OS) and progression free survival (PFS) used log rank test. Results Of the 78 patients analyzed, 49 (62.8%) received a PNA (44 with cladribine and 5 with pentostatin) and 29 (37.2%) received a PNA+R (25 with cladribine and 4 with pentostatin) as second line treatment for r/r HCL. Among the PNA+R cohort, the median number of R doses was 8 (range 1-8). R was administered concurrently in 35% and sequentially in 65% of PNA+R treated patients (N=20 with available data). Baseline characteristics were similar between the PNA and PNA+R cohorts. The median age at diagnosis in the PNA cohort was 52 yo (range 49-87) and 49 yo (range 30-79) in the PNA+R cohort (P=0.62). In the PNA cohort, 36% of patients were female and 64% male vs. 40% and 60%, respectively in the PNA+R cohort (P=0.79). There was no difference in the median time from initial treatment to relapse between the PNA vs. PNA+R cohort [59 months (4-273) vs 61 months (1-99), P=0.29]. At the time of relapse, age, hemoglobin, WBC, ANC, platelet count, and LDH showed no statistical difference between cohorts. Median follow-up for living patients was 57 months (1-197). Median time to best response after second line therapy was 2.4 months (1.0-30.0) in the PNA cohort and 1.2 months (1.0-11) in the PNA+R cohort (P=0.12). Among cases with known responses after second line treatment (N = 50), there was no difference in CR or PR for the PNA vs PNA+R cohorts (93% and 3.4% vs. 95% and 0%, respectively, P = 0.99). Six patients died, 3 from each cohort. Cause of death was due to septic shock in 1 patient and unknown in 5. As shown in the accompanying Figure, there was no difference in median PFS [62 months (95% CI 43.8-not reached) vs. 65 months (95% CI 60-not reached)] or 5-year OS [98% (95% CI 0.93-1) vs. 93% (95% CI 0.8-1), P=0.118] in the PNA vs. PNA+R cohorts, respectively. Conclusion Patients with r/r HCL after PNA frontline treatment who receive second line PNA or PNA+R have similar PFS and excellent OS. To our knowledge, this is the largest study evaluating the role of R in treatment of r/r HCL and suggests that there is no clinically discernable advantage to the addition of R to PNA therapy at the time of first re-treatment. The results of this study should be interpreted within the context of a recently reported prospective trial demonstrating improved minimal residual disease-free state with concurrent vs. sequential R with PNA in treatment naïve HCL patients (Chihara, et al. JCO, 37, 2019 (suppl; abstr 7003)). Disclosures Pinilla Ibarz: Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Sanofi: Speakers Bureau; Teva: Consultancy; Bayer: Speakers Bureau; TG Therapeutics: Consultancy. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy. Shadman:Sunesis: Research Funding; AbbVie: Consultancy, Research Funding; Atara Biotherapeutics: Consultancy; Sound Biologics: Consultancy; Celgene: Research Funding; Genentech: Consultancy, Research Funding; BeiGene: Research Funding; Astra Zeneca: Consultancy; Mustang Bio: Research Funding; Acerta Pharma: Research Funding; TG Therapeutic: Research Funding; ADC Therapeutics: Consultancy; Verastem: Consultancy; Pharmacyclics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Brander:Genentech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Research Funding; DTRM Biopharma: Research Funding; MEI: Research Funding; Acerta: Research Funding; Tolero: Research Funding. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Tallman:Biosight: Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Cellerant: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hill:Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Takeda: Research Funding; TG therapeutics: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding.

Introduction: Graft failure remains a major obstacle to the success of allo-HSCT. Rates of graft failure are reported to be 2% in recipients of HLA identical grafts, 9% in those with an unrelated donor, and up to 12.3% in those with an HLA-mismatched related donor (0-3 antigen mismatched). Graft failure is associated with high mortality due to prolonged cytopenia's leading to significant anemia, bleeding, and infection. Successful management of graft failure usually requires a second transplant to restore normal hematopoiesis. The selection of a preparative regimen presents a challenge in these patients who have recently undergone myelosuppressive therapy prior to the failed transplant maneuver. We have employed the use of a minimally myelosuppressive regimen consisting of a single dose of pentostatin with a low dose of total body irradiation (TBI) as conditioning prior to a second allogeneic transplant for patients who experienced primary graft rejection. Methods: Under an IRB-approved retrospective study, we describe 4 consecutive patients with graft failure after allogeneic stem cell transplantation, who received a re-conditioning regimen consisting of pentostatin and low-dose TBI prior to second allo-HSCT. The median age of patients was 38 years (23-51). The conditioning regimens of the first transplant were myeloablative doses of cyclophosphamide/rabbit ATG; busulfan/fludarabine rabbit ATG/; busulfan/fludarabine; and fludarabine/melphalan (Table 1). Median cell doses for the first transplant were 7.7 x 10E6 CD34+ cells/kg and 104 x 10E6 CD3+ cells/kg. Two patients had primary graft rejection and 2 patients had secondary graft rejection. Patients with secondary graft rejection had initial hematopoietic engraftment of neutrophils on a median of 21 days and platelets on a median 61 of days post-transplant with subsequent declines in peripheral blood counts and chimerism studies showing loss of donor cell engraftment. The donor for the second transplant was the same in one patient and different in three patients and included a HLA-matched sibling in 2/4 patients and HLA-matched unrelated donor (URD) in 2/4 patients. One patient had two transplants from the same donor followed by a third transplant from a different HLA matched sibling donor. Conditioning for the second transplant in these cases consisted of pentostatin 4 mg/m2 as a single dose on day -3 and two fractions of 200 cGy TBI on days -2 and -1 as shown in Table 2. Results: Patients underwent the second (or third) donor allogeneic transplant at a median of 99 days following the first transplant. The second donor allograft contained a median of 9.6 x 10E6 CD34+ cells/kg and 390 x 10E6 CD3+ cells/kg. All recipients of the pentostatin-TBI conditioning regimen engrafted following transplantation of allogeneic stem cells (Table 2). Engraftment following the second transplant (or third transplant, in patient #1) occurred at a median of 22 days for neutrophils and 54 days for platelets, and all patients achieved 100% myeloid and lymphoid chimerism. Patients did not experience VOD/SOS or have severe mucositis, enteritis, or pulmonary toxicity, and were hospitalized a median of 39 days from the second transplant. All four patients achieved normal blood counts following the second transplant. One patient died unexpectedly of an apparent infection following full donor hematopoietic reconstitution. Three of the four patients undergoing a second transplant using pentostatin/TBI conditioning are alive without evidence for disease relapse or graft rejection at a median follow-up of 3.5 years, with none of these patients experiencing severe acute or chronic GvHD. Conclusion: Single dose pentostatin combined with low-dose TBI represents an effective and well-tolerated conditioning regimen that facilitates engraftment of a second allogeneic transplant in patients who experienced primary or secondary graft rejection. The enhanced therapeutic efficacy of this reduced-intensity regimen that allowed consistent donor-derived hematopoietic engraftment after initial allo-graft rejection warrants further study. Disclosures Langston: Astellas Pharma: Other: Research Support; Incyte: Other: Research Support; Jazz Pharmaceuticals: Other: Research Support; Chimerix: Other: Research Support; Takeda: Other: Research Support; Kadmon Corporation: Other: Research Support; Novartis: Other: Research Support; Bristol Myers Squibb: Other: Research Support. Waller:Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: the use of pentostatin as part of a conditioning regimen

Hematopoietic-cell-transplantation-specific-comorbidity-index (HCT-CI) has been reported as a predictor of survival in allogeneic-transplant recipients; however its validity has recently been challenged. We evaluated the association of HCT-CI with survival of transplant recipients who underwent reduced-intensity-conditioning (RIC) with photopheresis, pentostatin, and total-body-irradiation. Median age of 103 patients selected was 55 years. Most patients (58.3%) had high (≥ 3) HCT-CI. Median OS was 298 days. Age, disease-type, disease-status, HCT-CI correlated with survival on bivariate analysis. On multivariate analysis, only HCT-CI was significantly associated with OS (low HCT-CI HR=0.29, CI 0.091-0.886; intermediate HCT-CI HR=0.41, CI 0.226-0.752). Our findings suggest HCT-CI as an independent predictor of survival in the setting of RIC transplants.

BACKGROUND Although rituximab-based chemoimmunotherapy (CIT) has substantially improved clinical outcomes in chronic lymphocytic leukemia (CLL), only 40% to 50% of patients achieve a complete remission (CR). There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a fully human anti-CD20 monoclonal antibody with greater apparent single-agent activity than rituximab in CLL patients. METHODS Previously untreated CLL patients in need of therapy received 6 cycles of CIT induction with pentostatin, cyclophosphamide, and ofatumumab (PCO) followed by response assessment. RESULTS Of the 48 patients enrolled, 77% completed PCO induction. Adverse events during induction included grade 3+ hematologic toxicity (27%) and grade 3+ nonhematologic toxicity (23%). Median CD4 count after induction and 6 months later were 186 × 106/L and 272 × 106/L. The overall response rate was 96% (46 of 48 patients), and the CR rate was 46% (22 of 48 patients). Among the 38 patients who underwent minimal residual disease evaluation, 7 (18%) were negative for minimal residual disease. After median follow-up of 24 months, 10 (21%) patients have progressed and 8 (17%) have required retreatment. The efficacy and toxicity of ofatumumab-based CIT compare favorably to our historical trials of rituximab-based CIT using an identical chemotherapy backbone (n = 64). Time to retreatment also appeared longer for ofatumumab-based CIT (free of retreatment at 24 months: 86% [95% confidence interval = 75-99] versus 68% [95% confidence interval = 56-81] for rituximab-based CIT). CONCLUSIONS Ofatumumab-based CIT is well tolerated in patients with previously untreated CLL. The efficacy of ofatumumab-based CIT compares favorably to historical trials of rituximab-based CIT, suggesting randomized trials comparing ofatumumab-based CIT and rituximab-based CIT should be considered. Cancer 2013;119:3788–3796. © 2013 American Cancer Society.

One limitation of reduced-intensity preparative regimens is potential for graft failure. We have developed a regimen that targets CD4(+) lymphodepletion to ensure early and durable engraftment. The primary endpoint was achievement of ≥50% CD3(+) donor chimerism by day +28. Forty-two patients (median age, 53 years; range, 29 to 73 years) received pentostatin 4 mg/m(2) i.v. on days -28, -21, and -14 when the CD4(+) cell count was100 cells/μL and on days -4 and -3 regardless of CD4(+) level. Rituximab 375 mg/m(2) was administered to patients with CD20(+) malignancies on days -21, -14, -7, +1, and +8. Busulfan 200 mg/m(2) i.v. was administered on days -4 and -2 at a dose to target a cumulative AUC dose of 16,000 (±10%) μmol·min/L. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 86% of patients. Donors were matched-related (47%), matched unrelated (43%), or mismatched unrelated (10%). Chronic lymphocytic leukemia (45%) and follicular non-Hodgkin lymphoma (14%) were the most common diagnoses. Disease status at initiation of the preparative regimen was complete remission in 22%, partial response in 55%, and stable/progression in 24%. The median percent CD4(+) cell count decrease from baseline (day -28) was 52% to day -21, 66% to day -14, 62% to day -7, and 91% to day 0. At day +28, all 42 patients (100%) had ≥50% CD3(+) donor chimerism. No patient experienced graft failure. Overall response rate was 82% (complete remisson, 67%). The day +100 cumulative incidence of grade II-IV acute GVHD was 59% (grade III-IV acute GVHD, 19%), and the 2 year cumulative incidence of chronic GVHD was 69% (moderate/severe, 58%). Nonrelapse mortality was 2% at day +100 and 17% at 2 years. Two-year PFS was 55%, and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse.

While in last four decades significant strides have been made in understanding the biology of graft-versus-host disease (GvHD) and its prevention, little is known about the different populations of lymphocytes and the changes in response to treatment for this condition. BMT-CTN 0302 was a randomized phase II clinical trial in the Blood and Marrow Transplant Clinical Trials Network that assessed the efficacy of combination therapy with steroids plus 1 of 4 other agents: pentostatin, mycophenolate mofetil, etanercept, or denileukin diftitox, in patients with acute GvHD. Patients enrolled in the study had their blood analyzed by flow cytometry on days 0, 14, and 28 of therapy to enumerate the number of total lymphocytes, T cells, B cells and lymphocytes expressing activation markers. Baseline lymphocyte total counts and the subpopulations were similar in the four treatment arms. Responding patients at day 28 had a smaller decrease in their total CD45+ cells (p=0.005) compared to non-responding patients. In univariate analysis those who developed chronic GvHD had significantly more CD8+ cells at day 14 compared to those without it (p =0.005). There was no significant association between baseline lymphocyte counts and survival. In univariate analysis, among patients with higher lymphocyte counts at days 14 and 28, there was a trend towards better survival at day 180 although this did not reach the pre-determined threshold for significance. Among the four different treatment arms, we found no significant differences in lymphocyte total or subpopulation counts and no notable influence on outcomes.

Pulmonary endothelial cell (EC) apoptosis has been implicated in the pathogenesis of emphysema. Cigarette smoke (CS) causes lung EC apoptosis and emphysema. In this study, we show that CS exposure increased lung tissue adenosine levels in mice, an effect associated with increased lung EC apoptosis and the development of emphysema. Adenosine has a protective effect against apoptosis via adenosine receptor-mediated signaling. However, sustained elevated adenosine increases alveolar cell apoptosis in adenosine deaminase-deficient mice. We established an in vitro model of sustained adenosine exposure by incubating lung EC with adenosine in the presence of an adenosine deaminase inhibitor, deoxycoformicin. We demonstrated that sustained adenosine exposure caused lung EC apoptosis via nucleoside transporter-facilitated intracellular adenosine uptake, subsequent activation of p38 and JNK in mitochondria, and ultimately mitochondrial defects and activation of the mitochondria-mediated intrinsic pathway of apoptosis. Our results suggest that sustained elevated adenosine may contribute to CS-induced lung EC apoptosis and emphysema. Our data also reconcile the paradoxical effects of adenosine on apoptosis, demonstrating that prolonged exposure causes apoptosis via nucleoside transporter-mediated intracellular adenosine signaling, whereas acute exposure protects against apoptosis via activation of adenosine receptors. Inhibition of adenosine uptake may become a new therapeutic target in treatment of CS-induced lung diseases.

Summary Background Recent trials suggest improved response rates for purine analogues compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a survival advantage. Thus, a systematic Cochrane review may be able to further define the role of purine analogues in the first-line treatment of B-CLL. Methods Randomized controlled trials comparing single-agent purine analogues with alkylator-based regimens were included. Medical databases (Cochrane Library, MEDLINE, EMBASE), conference proceedings and trial registers were searched. We included full-text and abstract publications as well as unpublished data. Relative risks (RR) and hazard ratios (HR) were calculated under a fixed-effects model, clinical and statistical heterogeneity was examined with sensitivity analyses and meta-regression. If applicable, numbers needed to treat or harm (NNT, NNH) were also determined. Findings Five trials with 1838 randomized patients were included. Importantly, four trials had a cross-over design. There was a trend for improved overall survival for patients receiving purine analogues as initial therapy but statistical significance was just not reached (HR 0.89 [95% CI 0.78–1.01]). The RR for achieving an overall (RR 1.22 [95% CI 1.13–1.31]; NNT 8 [95% CI 6–13]) and complete response (RR 1.94 [95% CI 1.65–2.28]; NNT 6 [5–8]) was significantly improved, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61–0.82]). Incidence of grade III/IV infections (RR 1.83 [95% CI 1.30–2.58]; NNH 20 [95% CI 12.5–50]) and haemolytic anaemia (RR 3.36 [95% CI 1.27–8.91]; NNH 21 [95% CI 6–185]) was significantly higher in patients receiving purine analogues. Interpretation Despite significantly increased response rates and longer progression-free survival with purine analogues as first-line therapy, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of purine analogues augments the risk for grade III/IV infections and haemolytic anaemia.

Background Patients who undergo allogeneic stem cell transplantation and subsequent radiation therapy uncommonly develop graft-versus-host disease within the irradiated area. We quantified the incidence of this complication, which is a novel contribution to the field. From 2010 to 2014, 1849 patients underwent allogeneic stem cell transplantation, and 41 (2 %) received radiation therapy afterward. Of these, two patients (5 %) developed graft-versus-host disease within the irradiated tissues during or immediately after radiation therapy. Case presentation The first patient is a 37-year-old white man who had Hodgkin lymphoma; he underwent allogeneic stem cell transplantation from a matched unrelated donor and received radiation therapy for an abdominal and pelvic nodal recurrence. After 28.8 Gy, he developed grade 4 gastrointestinal graft-versus-host disease, refractory to tacrolimus and steroids, but responsive to pentostatin and photopheresis. The other patient is a 24-year-old white man who had acute leukemia; he underwent allogeneic stem cell transplantation from a matched related donor and received craniospinal irradiation for a central nervous system relapse. After 24 cobalt Gy equivalent, he developed severe cutaneous graft-versus-host disease, sharply delineated within the radiation therapy field, which was responsive to tacrolimus and methylprednisolone. Conclusions We conclude that graft-versus-host disease within irradiated tissues is an uncommon but potentially serious complication that may follow radiation therapy in patients who have undergone allogeneic stem cell transplantation. Clinicians must be aware of this complication and prepared with strategies to mitigate risk. Patients who have undergone allogeneic stem cell transplantation represent a unique population that may offer novel insight into the pathways involved in radiation-related inflammation.

Aims Extracellular nucleotides and adenosine that are formed or degraded by membrane-bound ecto-enzymes could affect atherosclerosis by regulating the inflammation and thrombosis. This study aimed to evaluate a relation between ecto-enzymes that convert extracellular adenosine triphosphate to adenine dinucleotide phosphate, adenosine monophosphate, adenosine, and inosine on the surface of the vessel wall with the severity or progression of experimental and clinical atherosclerosis. Furthermore, we tested whether the inhibition of adenosine deaminase will block the development of experimental atherosclerosis. Methods and results Vascular activities of ecto-nucleoside triphosphate diphosphohydrolase 1, ecto-5’-nucleotidase, and ecto-adenosine deaminase (eADA) were measured in aortas of apolipoprotein E-/- low density lipoprotein receptor (ApoE-/-LDLR-/-) and wild-type mice as well as in human aortas. Plaques were analysed in the entire aorta, aortic root, and brachiocephalic artery by Oil-Red O and Orcein Martius Scarlet Blue staining and vascular accumulation of macrophages. The cellular location of ecto-enzymes was analysed by immunofluorescence. The effect of eADA inhibition on atherosclerosis progression was studied by a 2-month deoxycoformycin treatment of ApoE-/-LDLR-/- mice. The vascular eADA activity prominently increased in ApoE-/-LDLR-/- mice when compared with wild type already at the age of 1 month and progressed along atherosclerosis development, reaching a 10-fold difference at 10 months. The activity of eADA correlated with atherosclerotic changes in human aortas. High abundance of eADA in atherosclerotic vessels originated from activated endothelial cells and macrophages. There were no changes in ecto-nucleoside triphosphate diphosphohydrolase 1 activity, whereas ecto-5’-nucleotidase was moderately decreased in ApoE-/-LDLR-/- mice. Deoxycoformycin treatment attenuated plaque development in aortic root and brachiocephalic artery of ApoE-/-LDLR-/- mice, suppressed vascular inflammation and improved endothelial function. Conclusions This study highlights the importance of extracellular nucleotides and adenosine metabolism in the atherosclerotic vessel in both experimental and clinical setting. The increased eADA activity marks an early stage of atherosclerosis, contributes to its progression and could represent a novel target for therapy.

The purine analogs, pentostatin and cladribine, induce high remission rates when used as first-line monotherapy for hairy cell leukemia (HCL); however, patients continue to relapse. Re-treatment with the same or alternate purine analog produces lower response rates and a shorter duration of response. Fludarabine is another purine analog widely used in indolent lymphoid cancers, often in combination with rituximab, but there are few reports of its use in HCL. We identified 15 patients treated in British Columbia with fludarabine and rituximab (FR) from 2004 to 2010 for relapsed/refractory HCL after first-line cladribine (n = 3) or after multiple lines of therapy (n = 12). All patients with available response data responded to FR. With median follow-up of 35 months, 14 patients remain progression-free, whereas 1 patient has developed progressive leukemia and died. Five-year progression-free and overall survivals are 89% and 83%, respectively. FR is a safe and effective therapeutic option for relapsed/refractory HCL.