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Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder characterized by pancytopenia, splenomegaly and increased susceptibility to infections. In 2011, BRAF gene mutation was identified in almost all the patients with the classical type of HCL. The purine analogs cladribine and pentostatin induce long-term remission in the majority of patients, and they remain the standard treatment for this type of leukemia. However, more than half of patients in complete response relapse over the long term, with a quarter of them relapsing within the first five years. Recently, new drugs have been developed and have demonstrated efficacy in refractory or relapsed HCL. The immunotoxin Moxetumomab pasudotox was registered for HCL in 2018. The BRAF kinase inhibitors vemurafenib and dabrafenib, as well as the Bruton kinase inhibitor ibrutinib, are also proven highly effective in clinical trials.

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.

Objectives.—To assess mortality and survival analysis for patients with hairy cell leukemia, taking into consideration the effect of new therapies. Background.—Hairy cell leukemia (HCL) is a chronic B-cell disorder and an uncommon malignancy. Initially, therapeutic options were limited, and outcomes were poor. However, with the introduction of alpha interferon in 1984, followed by two purine nucleoside analogues pentostatin (1986) and cladribine (1990) and more recently, rituximab, a monoclonal antibody, HCL outcomes have improved, translating HCL from a disease with limited treatment options to a highly treatable disease with a near-normal survival. Methods.—A SEER-17 database survival analysis was conducted on patients diagnosed with HCL in the US. Using the International Classification of Diseases code for HCL (9940), the SEER database was interrogated for patients diagnosed from 1973-2013. Analysis was based on comparing the survival of patients in the last 4 decades to the expected survival population generated by the SEER data. Analysis using mortality and survival methodology was used to calculate the excess death rate (EDR), mortality ratios, and survival ratios. Results.—In patients with HCL diagnosed from 1973-1983 compared to those diagnosed from 1984-1993, the survival improved by 6% in the first year and reached 26% by year 5, 30% by year 10, 33% by the year 15, and 40% by year 20. Calculations of relative mortality showed a decrease in mortality from decade 1973-1983 to decade 1984-1993 of 66% in the first year, 96% by year 5, 66% by year 10, 46% by year 15, and 40% by year 20. Conclusions.—The survival of patients diagnosed with HCL has improved over the last 3 decades, with a significant benefit being seen since 1984. Thanks to the introduction of newer drugs, the outcome of patients with HCL has been transformed into a highly treatable form of leukemia, and patients now have a near-normal life expectancy.

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.

Hairy cell leukemia (HCL) is an indolent B-cell malignancy, with long-term responses to purine analogs, but with decreasing efficacy and increasing toxicity with repeated courses. Leukemic cells express CD22, CD20, CD25, tartrate-resistant acid phosphatase (TRAP), annexin 1A (Anxa1), and BRAF V600E mutation. HCLv, lacking CD25, Anxa1, TRAP, and BRAF V600E, is more aggressive and less purine analog-sensitive. A molecularly defined IGHV4-34+ variant is also resistant whether HCL or HCLv immunophenotypically. Traces of HCL cells, termed minimal residual disease (MRD), accompany most with complete remission (CR) and may cause relapse. Rituximab has limited single-agent activity, but frequent CR without MRD when combined with purine analog, albeit with chemotherapy toxicities. The anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox can achieve MRD-negative CR in multiply relapsed HCL without chemotherapy toxicities and was FDA approved in 2018 as Lumoxiti. Investigational oral non-chemotherapy options also include Vemurafenib or Dabrafenib/Trametinib targeting BRAF V600E ± MEK, and Ibrutinib targeting Bruton's tyrosine kinase.

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.

Hairy cell leukemia (HCL) is an indolent B-cell malignancy with excellent initial response to purine analogs pentostatin or cladribine, but patients are rarely, if ever, cured. Younger patients will usually need repeat chemotherapy which has declining benefits and increasing toxicities with each course. Targeted therapies directed to the BRAF V600E mutation and Bruton’s tyrosine kinase may be helpful, but rarely eradicate the minimal residual disease (MRD) which will eventually lead to relapse. Moxetumomab pasudotox (Moxe) is an anti-CD22 recombinant immunotoxin, which binds to CD22 on HCL cells and leads to apoptotic cell death after internalization and trafficking of the toxin to the cytosol. Phase I testing achieved a complete remission (CR) rate of 57% in relapsed/refractory HCL. Most CRs were without MRD and eradication of MRD correlated with prolonged CR duration. Patients were often MRD-free after five years. Important mild-moderate toxicities included capillary leak and hemolytic uremic syndromes which could be prevented and managed conservatively. A phase 3 trial met its endpoint of durable CR with acceptable toxicity, leading to FDA approval of Moxe for relapsed/refractory HCL, under the name Lumoxiti. Moxe combined with rituximab is currently being evaluated in relapsed/refractory HCL to improve the rate of MRD-free CR.

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

Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is associated with chronic inflammatory disorders. We present an indolent pancolonic MALT lymphoma occurring in a 39-year-old female with history of autoimmune hepatitis requiring liver transplant in 1997 and ulcerative colitis diagnosed in 2004. Random biopsies from a grossly unremarkable surveillance colonoscopy in 2015 revealed a dense monomorphic plasmacytoid infiltrate causing expansion of lamina propria without significant crypt infiltration or destruction. These cells were positive for CD79a and CD138 and showed lambda restriction; however, CD20, CD43, CD56, HHV8, and EBER were negative. A similar pancolonic infiltrate was identified in all prior colorectal biopsies from 2010 and 2012 upon retrospective review. Subsequent computed tomography of the abdomen revealed no bowel wall thickening nor enlarged lymph nodes. Bone marrow revealed involvement consistent with stage IV disease. Biopsies from 2010 and 2015 demonstrated clonal immunoglobulin gene rearrangement. MYD88 mutation was not detected. The overall features were indicative of MALT lymphoma. Although low-grade B-cell lymphomas are not considered part of the post-transplant lymphoproliferative disorder spectrum, such cases have been reported, and are typically EBV-negative. Patient underwent treatment with pentostatin for her MALT lymphoma reaching a sustained remission despite additional immunosuppression for resurgent hepatic dysfunction. To our knowledge, this is the first reported case of EBV-negative pancolonic MALT lymphoma with plasmacytic differentiation post liver transplant presenting in an indolent, asymptomatic fashion with persistence for greater than five years successfully managed without compromising the patient's liver transplant.

Patients with hairy cell leukaemia (HCL) have highly favourable outcomes after purine analogue therapy. However, most patients subsequently relapse and require re-treatment. A minority of patients develop purine analogue-refractory disease. Targeted therapies have improved outcomes for such patients. Recently, the BRAF V600E mutation was identified in most patients with classical HCL, resulting in constitutive mitogen-activated protein kinase pathway activation; impressive responses are achieved in heavily pre-treated patients with BRAF inhibition. The CD22-targeted immunoconjugate moxetumomab pasudotox and BTK inhibitor ibrutinib also achieve responses in relapsed and refractory patients. HCL variant and the IGHV4-34 molecular variant of HCL lack BRAF mutation and have inferior outcomes with standard purine analogue therapy. The addition of rituximab to purine analogues achieves very high rates of minimal residual disease-negative complete remission and improves outcomes for patients with HCL variant. Given the rarity of HCL, optimal integration of novel therapies into treatment algorithms will require well-designed, collaborative studies.

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.

T-cell prolymphocytic leukemia is a postthymic mature lymphoid leukemia known to be associated with poor outcome. The median age at diagnosis is 61 years, and the clinical picture includes high whi...

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.

This is the first report of a complete remission in aggressive T-cell large granular lymphocytic (T-LGL) leukemia after treatment with pentostatin. The aggressive variant of the disease is rare, and traditional therapies include immunosuppressive agents, however, there is no standard consensus for treatment. Cytotoxic chemotherapy has led to remission in a few reported cases. We present this unique case as an alternative treatment for individuals refractory to chemotherapy. A 55-year-old African American male with hypertension, type II diabetes mellitus, hyperlipidemia, and gout presented with symptoms of multiple ecchymosis, fatigue, and weight loss. He was found to have splenomegaly (SM) and significant leukocytosis to 101 k/µL with 30% blasts on peripheral smear. Following bone marrow aspiration and biopsy with flow cytometry, he was diagnosed with aggressive T-LGL leukemia. The chemotherapy regimen hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) was initially chosen based on his clinical presentation but was refractory to treatment. His therapy was changed to alemtuzumab; however, patient tolerated poorly and did not respond. Pentostatin was added to alemtuzumab with improvement in clinical symptoms and laboratory parameters. The patient was transitioned to pentostatin monotherapy and achieved complete remission after 1 month. This report provides support for pentostatin as an effective treatment for patients with aggressive T-cell malignancies refractory to cytotoxic chemotherapy. Pentostatin has previously been studied to treat T-cell prolymphocytic leukemia (T-PLL), hairy cell leukemia, and marginal zone lymphoma. This case suggests an alternative, well-tolerated option that could be considered for initial therapy of aggressive T-LGL leukemia.

// 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.

Immunotoxins are targeted anticancer therapeutics that kill cancer cells using a cytotoxic bacterial toxin payload. Their development for use in solid tumor malignancies was delayed due to issues with their immunogenicity and limited therapeutic window. However, new research has rejuvenated the field. Coadministration with a lymphocyte-depleting regimen of pentostatin and cyclophosphamide can delay antidrug antibody formation, increasing the number of treatment cycles that patients can receive and resulting in durable responses in heavily pretreated patients. In addition, a new generation of immunotoxin molecules with reduced immunogenicity and nonspecific toxicity has been developed through protein engineering techniques, and one has recently entered the clinic. In preclinical studies in mouse models, these new agents are effective against many tumor types as single agents, and also produce synergistic antitumor responses in combination with chemotherapy. These new immunotoxins have renewed excitement in the field and may prove a promising addition to the targeted therapy repertoire. Clin Cancer Res; 22(5); 1055–8. ©2015 AACR.

Success in the treatment of patients with hairy cell leukemia (HCL) over the last several decades is largely due to the high efficacy of the nucleoside analogs, cladribine and pentostatin. However, the relapse-free survival curves have not shown a plateau and many patients treated with these agents will eventually relapse. Although better understanding of the pathogenic mechanisms in HCL have led to effective and novel options for the treatment of relapse, long term durability of the responses obtained with these agents still remains unclear. Combination of nucleoside analogs with monoclonal antibodies such as rituximab has been shown to be safe and effective and has the potential to supersede the nucleoside analogs as the frontline strategy. Such chemo-immunotherapy approaches are under further investigation and will have to be assessed with socioeconomic considerations in mind. Other novel monoclonal antibodies, approved for the treatment of other lymphoid neoplasms, may also be considered for future studies of chemo-immunotherapy.

This brief review highlights the sequence of therapeutic milestones and advances in our understanding of the biology of hairy cell leukemia (HCL) with a focus on recent molecular findings and how these may be applied to improve disease outcomes in the future. Targeted therapy is discussed in the context of the recently identified BRAF mutation and other genetic findings.

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.

The aim of this study was to evaluate the therapeutic efficacy and safety of using 3′deoxyadenosine (Cordycepin – adenosine analogue) combined with deoxycoformycin (Pentostatin – an adenosine deaminase inhibitor) in mice infected with Trypanosoma evansi. We show that the combination of Cordycepin (2.0 mg kg−1) and Pentostatin (0.2, 0.5, 1.0, 2.0 mg kg1) is effective in the clearance of T. evansi, although at the higher concentrations of Pentostatin 2 mg kg−1 some toxicity was observed in the liver and kidney. Since the Cordycepin 2.0 mg kg−1 and Pentostatin 0.2 mg kg−1 combination was effective and had low toxicity, we recommend this as a therapeutic option for a T. evansi mouse model.

Hairy cell leukemia (HCL) is a lymphoproliferative B-cell disorder characterized by pancytopenia, splenomegaly, and characteristic cytoplasmic hairy projections. Precise diagnosis is essential in order to differentiate classic forms from HCL variants, such as the HCL-variant and VH4-34 molecular variant, which are more resistant to available treatments. The current standard of care is treatment with purine analogs (PAs), such as cladribine or pentostatin, which provide a high rate of long-lasting clinical remissions. Nevertheless, ~30%-40% of the patients relapse, and moreover, some of these are difficult-to-treat refractory cases. The use of the monoclonal antibody rituximab in combination with PA appears to produce even higher responses, and it is often employed to minimize or eliminate residual disease. Currently, research in the field of HCL is focused on identifying novel therapeutic targets and potential agents that are safe and can universally cure the disease. The discovery of the BRAF mutation and progress in understanding the biology of the disease has enabled the scientific community to explore new therapeutic targets. Ongoing clinical trials are assessing various treatment strategies such as the combination of PA and anti-CD20 monoclonal antibodies, recombinant immunotoxins targeting CD22, BRAF inhibitors, and B-cell receptor signal inhibitors.

While the renal complications of plasma cell dyscrasia have been well-described, most information in patients with chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis is derived from case reports. This is a retrospective analysis of patients with chronic lymphocytic leukemia or monoclonal B-cell lymphocytosis who underwent kidney biopsy for renal insufficiency and/or nephrotic syndrome. Between January 1995 and June 2014, 49 of 4,024 (1.2%) patients with chronic lymphocytic leukemia (n=44) or monoclonal B-cell lymphocytosis (n=5) had a renal biopsy: 34 (69%) for renal insufficiency and 15 (31%) for nephrotic syndrome. The most common findings on biopsy were: membranoproliferative glomerulonephritis (n=10, 20%), chronic lymphocytic leukemia interstitial infiltration as primary etiology (n=6, 12%), thrombotic microangiopathy (n=6, 12%), and minimal change disease (n=5, 10%). All five membranoproliferative glomerulonephritis patients treated with rituximab, cyclophosphamide and prednisone-based regimens had recovery of renal function compared to 0/3 patients treated with rituximab with or without steroids. Chronic lymphocytic leukemia infiltration as the primary cause of renal abnormalities was typically observed in relapsed/refractory patients (4/6). Thrombotic microangiopathy primarily occurred as a treatment-related toxicity of pentostatin (4/6 cases), and resolved with drug discontinuation. All cases of minimal change disease resolved with immunosuppressive agents only. Renal biopsy plays an important role in the management of patients with chronic lymphocytic leukemia or monoclonal B-cell lymphocytosis who develop renal failure and/or nephrotic syndrome.

Summary We conducted a prospective phase II trial of pentostatin, cyclophosphamide and rituximab as initial therapy for patients with previously untreated advanced stage low-grade or indolent B-cell lymphomas (iNHLs). Of 83 evaluable patients, 91·6% attained an overall response and 86·8% a complete or unconfirmed complete response. The 3-year progression-free survival (PFS) and overall survival rates were 73% and 93%, respectively. The 3-year PFS rate was significantly different for different diagnoses (P = 0·01): 83% [95% confidence interval (CI): 0·72, 0·96] for follicular lymphomas, 73% (95% CI: 0·54, 1·0) for marginal zone lymphomas and 61% (95% CI: 0·46, 0·81) for small lymphocytic lymphomas. The most common adverse events were haematological. Of 509 cycles of chemotherapy administered, grade 3 or 4 neutropenia was reported in 68 cycles (13% of cycles administered) and most frequently occurred during cycles 4–6. This is the first report demonstrating the effectiveness of pentostatin, cyclophosphamide and rituximab in patients with previously untreated iNHLs, including those over 60 years of age.

Hairy cell leukemia was initially described as a distinct entity in 1958. It is rare B-cell malignancy characterized by an indolent course. Advances in the treatment and understanding of the biology of hairy cell leukemia have made the disease exquisitely amenable to treatment. This review summarizes the present understanding of hairy cell leukemia with a particular focus on the development of novel and targeted approaches to treatment.

Many drugs have been reported to cause thrombotic microangiopathy (TMA), often described as thrombotic thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS). We recently established criteria to evaluate the evidence for a causal association of a drug with TMA and then we systematically reviewed all published reports of drug-induced TMA (DITMA) to determine the level of evidence supporting a causal association of the suspected drug with TMA. On the basis of this experience, we used these evaluation criteria to assess the Oklahoma TTP-HUS Registry patients who had been previously categorized as drug-induced, 1989-2014. We also reviewed the experience of the BloodCenter of Wisconsin with testing for drug-dependent antibodies reactive with platelets and neutrophils in patients with suspected immune-mediated DITMA, 1988-2014. Among 58 patients in the Oklahoma Registry previously categorized as drug-induced (15 suspected drugs), 21 patients (three drugs: gemcitabine, pentostatin, quinine) had evidence supporting a definite association with TMA; 19 (90%) of the 21 patients had quinine-induced TMA. The BloodCenter of Wisconsin tested 40 patients with suspected DITMA (eight drugs); drug-dependent antibodies, supporting a definite association with TMA, were identified in 30 patients (three drugs: oxaliplatin, quinine, vancomycin); 28 (93%) of the 30 patients had quinine-induced TMA. Combining the data from these two sources, 51 patients (five drugs) have been identified with evidence supporting a definite association with TMA. DITMA was attributed to quinine in 47 (92%) of these 51 patients.

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.