Cladribine For Hairy Cell Leukemia Research Articles

Prospective long-term follow-up after first-line subcutaneous cladribine in hairy cell leukemia: a SAKK trial

AbstractHairy cell leukemia (HCL) remains an incurable disease. However, first-line treatment with either intravenous or subcutaneous cladribine generally leads to long-lasting remissions. Although there are excellent long-term data for intravenous application, similar data regarding subcutaneous administration are lacking. We therefore analyzed the long-term outcome of 3 prospective multicenter clinical trials on subcutaneous cladribine performed by the Swiss Group for Clinical Cancer Research (SAKK), which recruited 221 patients with classical HCL between 1993 and 2005. Median overall survival from start of treatment was not reached. Pretreatment anemia, higher Eastern Cooperative Oncology Group score, and higher age were associated with poorer overall survival in multivariable analysis, whereas early progression at 24 and 36 months had no significant impact on overall survival. Second-line treatment was necessary in 53 (23.7%) patients after a median of 5 (range, 0.2-20.4) years, and first retreatment was mainly monotherapy with cladribine (66%) or rituximab (15.1%) or a combination of these drugs (15.1%). A total of 44 (19.9%) patients developed second primary malignancies with a median time to occurrence of 5.7 (range, 0.01-17.5) years. Second primary malignancies were the main cause for death (14; 27.5%). Compared with a matched normal Swiss population, the incidence of second primary malignancies was not increased. However, survival of patients with HCL was slightly inferior by comparison (P = .036). In conclusion, the outcome of HCL patients treated with subcutaneous cladribine is excellent, and in most patients, 1 cycle of subcutaneous cladribine is sufficient for long-term disease control.

Primary peg-filgrastim prophylaxis versus filgrastim given “on demand” for neutropenia during therapy with cladribine for hairy cell leukemia

BackgroundMajor advances in the treatment of patients with hairy cell leukemia (HCL) have been made following the introduction of purine analogues. The major significant short-term toxicity of cladribine therapy are neutropenia and neutropenic fever (NF) which may be life-threatening. AimIn this retrospective study, we compared the incidence and duration of neutropenia and hospitalization in patients with HCL treated with cladribine followed by peg-filgrastim as primary prophylaxis versus daily filgrastim given “on demand” according to absolute neutrophil count (ANC). MethodsMedical records of patients with HCL diagnosed and followed in 12 medical centers in Israel during 1985–2015 were examined for details of disease at diagnosis. The efficacy of peg-filgrastim and filgrastim was assessed by evaluating the incidence of neutropenia (ANC < 1.0 × 10 [9]/L), number and length of hospitalizations, and number of days from the last day of therapy to recovery of ANC to >1.0 × 10 [9]/L. ResultsThe study population included 202 patients with HCL, 159 of whom (80.7%) were treated with cladribine; 78 patients (49%) required hospitalization for the administration of broad-spectrum antibiotics due to NF. Twenty-eight (19%) patients were treated with peg-filgrastim as primary prophylaxis, while 74 (64%) received filgrastim “on demand” due to neutropenia. Median length of hospitalization, and nadir duration were 8 and 18 days respectively (p = 0.71, p = 0.44). ConclusionsInfectious complications post-cladribine treatment remain high. No difference was found in terms of incidence of NF, number of febrile days, and nadir duration in patients receiving primary peg-filgrastim prophylaxis compared to filgrastim given on demand. Both approaches are justifiable, and the choice remains at the physician’s discretion.

Novel and Emerging Drugs for Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a challenging disease to treat with the majority of patients dying from their illness. While overall survival has been markedly prolonged in acute promyelocytic leukemia (APL), survival in younger adults with other subtypes of AML has only modestly improved over the last twenty years. Physicians who treat AML eagerly await drugs like Imatinib for chronic myeloid leukemia, Cladribine for hairy cell leukemia, and Rituximab for non-Hodgkin Lymphoma which have had an important impact on improving outcome. Recent research efforts have focused on refining traditional chemotherapeutic agents to make them more active in AML, targeting specific genetic mutations in myeloid leukemia cells, and utilizing novel agents such as Lenalidomide that have shown activity in other hematologic malignancies. Here, we focus on reviewing the recent literature on agents that may assume a role in clinical practice for patients with AML over the next five years.

Serum galactomannan (GM) assay for invasive aspergillosis (IA) in acute leukemia (AL) and hematopoietic stem cell transplantation (HSCT).

6538 Background: IA is a major cause of mortality in AL and HSCT. The objectives of this study were to determine the yield of GM assay for the diagnosis of probable IA, its temporal relationship with high-resolution computed tomographic scan (HRCT) scans and correlation with mortality in patients of AL and recipients of HSCT. Methods: Consecutive neutropenic episodes among inpatients aged ≥ 15 years with a diagnosis of AL and recipients of HSCT were prospectively evaluated over 1½ years. All patients received oral itraconazole or thrice weekly IV amphotericin B (AmB) as prophylaxis. Weekly serum GM assay was performed for all subjects. Optical density index (ODI) > 0.5 for two or more samples was defined as positive. Patients with persistent fever for ≥ 96 hours on intravenous antibiotics were evaluated with HRCT chest and received empiric AmB. IA was diagnosed according to EORTC 2008 guidelines and treated with therapeutic doses of voriconazole or AmB. Results: Of the 150 episodes enrolled, AL induction constituted 51.3% (AML 35.3%, ALL 16%), high-dose cytarabine 20%, autologous HSCT 24.7%, allogeneic HSCT 2.7% and cladribine for hairy cell leukemia 1.3% episodes. Forty-three episodes (28.7%) were diagnosed with IA: possible 25 (16.7%), probable 17 (11.3%) and proven 1 (0.7%). The yield of GM assay in diagnosing probable IA was 17/42 (39.5%). False-positivity of a single test was 54.2% but decreased to 11.2% with two results. Assessment of sensitivity was impaired due to the lack of proven cases. The lone proven case had 1/1 sample positive (ODI 2.17). In 88.2% of probable IA episodes GM was positive before HRCT at a median of 10 days (range, 1-16) earlier, while HRCT was positive before GM in the remaining 11.8% episodes at median of 3.5 days (range, 1-7) earlier. Of the 23 fatal episodes (15.3%), 17 had a diagnosis of IA. Considering only those episodes with ≥2 samples tested, fatality was 31.0% in those with at least 2 values positive for GM, compared to 13.2% in the episodes with < 2 GM samples positive (OR 2.96, 95% CI 1.09 – 8.00; p=0.04). Conclusions: In a population of high-risk patients, GM assay could identify patients with probable IA earlier than HRCT chest and also predicted a higher risk of death.

Mechanism of Action of Pentostatin and Cladribine in Hairy Cell Leukemia

Pentostatin (2′-deoxycoformycin; dCF) and cladribine (2-chlorodeoxyadenosine; CdA) are highly effective agents for the treatment of hairy cell leukemia. Although their precise mechanisms of action in this disease are still unknown, a number of mechanisms have been postulated. dCF is a potent inhibitor of adenosine deaminase (ADA), and treatment results in the accumulation of deoxyadenosine (dAdo) and adenosine (Ado) in the plasma. dAdo is phosphorylated by deoxycytidine kinase in lymphocytes to deoxyadenosine monophosphate (dAMP), which is subsequently converted to deoxyadenosine triphosphate (dATP). CdA is the chlorinated derivative of deoxyadenosine, is resistant to degradation by ADA, and accumulates in lymphocytes as CdATP. Both dATP and CdATP cause an initial accumulation of DNA strand breaks in lymphocytes and this results in the activation of p53, the release of cytochrome c from mitochondria, and apoptosis. CdA has several unique mechanisms of action over dAdo and these include the incorportation of CdATP into DNA, the inhibition of DNA polymerase β, and the phosphorylation of CdA to CdATP by deoxyguanosine kinase in mitochondria. These additional modes of action produce further DNA breaks in CdA-treated cells and explain the more potent activity of CdA compared to dCF and the greater myelosuppression with this agent. The cells die by apoptosis, but the DNA strand breaks also cause the activation of poly(ADP-ribose) polymerase (PARP), with resultant cellular depletion of nicotinamide adenine dinucleotide (NAD) and ATP. The induction of necrosis by PARP activation may explain the activity of these analogs in some patients with p53 mutations.

Combined Treatment with Splenectomy and Cladribine in Hairy Cell Leukemia in Taiwan: A Clinicopathologic Study of 5 Cases

Hairy cell leukemia (HCL) is a rare B-cell lymphoid malignancy that is characterized by the presence of hairy cells in the peripheral blood and bone marrow, pancytopenia and various degrees of splenomegaly. Very few reports have explored the clinicopathologic features and treatment outcome of HCL in Taiwan. Of 33 patients with malignant lymphoma who underwent splenectomy over a 10-year period (1996-2005), 5 cases of HCL were retrospectively studied. All cases presented with various degrees of splenomegaly. Pancytopenia was noted in 3 cases, and lymphadenopathy in 1. Typical hairy cells with positive tartrate-resistant acid phosphatase stain were noted in 2 cases. Only 3 cases could be diagnosed with HCL based solely on bone marrow findings. In contrast, all spleen specimens had characteristic pathologic features. All patients underwent splenectomy uneventfully, and cladribine was given at a median time of 2 months after splenectomy without significant side effects. Complete remission with durable response was documented in 4 patients (80%) with a median follow-up of 29 months (range, 4-96 months). The last patient experienced partial remission but was only followed up for 4 months. For the HCL patients in this study, splenectomy had a role not only in improving cytopenia but in aiding diagnosis. Cladribine is safe and highly effective for Taiwanese patients and should be considered as first-line treatment for HCL.

Potential Predictive Patterns of Minimal Residual Disease Detected by Immunohistochemistry on Bone Marrow Biopsy Specimens During a Long-term Follow-up in Patients Treated With Cladribine for Hairy Cell Leukemia

Minimal residual disease (MRD) in patients treated for hairy cell (HC) leukemia as assessed by immunohistochemistry has not been included routinely in evaluation of treatment results. To assess the presence of persistent HCs after treatment, as detected by immunohistochemistry, and to evaluate the correlation between the level of MRD and clinical outcome. Percentages of DBA.44-positive HCs were assessed on 116 biopsy specimens from 17 patients. The patients had a median follow-up of 55.4 months. Minimal residual disease was seen in 3 patterns. Group 1 (7 patients) had MRD levels ranging from "rare scattered suspicious HCs" to less than 1%. The MRD levels were stable throughout follow-up, and all patients remained in complete remission. Group 2 (6 patients) had MRD levels ranging from 1% to 5%, and 3 patients were in complete remission at 77.9, 63.8, and 108.0 months. Another patient showed evidence of disease activity (partial remission) at 47.6 months. Two other patients relapsed at 12.3 months and at 25.7 months, respectively, with greater than 1% HCs. Group 3 (4 patients) had MRD levels greater than 5%. Three patients relapsed at 11.3, 12.1, and 29.6 months, respectively, with greater than 5% HCs. The fourth patient had MRD levels of 5% at 14.6 months and 2% at 20.0 months but was subsequently lost to follow-up. Quantitative assessment of MRD may be of value in identifying patients at risk for relapse of hairy cell leukemia.

Pentostatin and Cladribine in Hairy Cell Leukemia- a Retrospective Comparison of a Large Series with Long Follow up.

Complete responses (CR) of up to 95% have been reported with both pentostatin and cladribine in patients with hairy cell leukemia (HCL). Although responses are durable, relapses occur even 10 years after treatment. No trial has compared pentostatin to cladribine for HCL. Furthermore, few series achieve sufficient maturity to answer the question: can these agents induce a cure in HCL? We reviewed retrospectively 219 patients with HCL (median follow up (FU) from diagnosis: 12.6 years) to compare pentostatin with cladribine in the treatment of HCL, and to assess the potential for cure in this disease. Diagnosis of HCL and exclusion of HCL-variant were confirmed by central review. Overall response to 1st line pentostatin (n=185) was 96% with CR of 81% and median FU of 10.8 (range 0.3–17.9) years. Response to cladribine was 100% with CR of 82%. No significant difference in response was seen with cladribine (n=34) at median FU of 7.2 (range 0.5–11.5) years. Median disease free survival (DFS) for both agents was 10 years. 38% of patients relapsed 4.9 (range 1–16) years and 4.4 (range 1–10) years after treatment with pentostatin and cladribine, respectively. Although responses were maintained for pentostatin and cladribine when used at 2nd (94% and 100% respectively) and 3rd line (100% and 100% respectively) treatment, CR decreased significantly with each sequential relapse through 70% to 45% (p≤0.01). Attainment of CR at 1st line treatment was significantly associated with increased DFS (p=0.000) as compared to those achieving only partial response (PR). [Display omitted] A similar result was seen at 2nd line therapy (p=0.000). DFS also showed a significant decline with sequential treatment (p=0.001) mirroring the reduced likelihood of achieving CR with increasing number of courses. There was some crossover of patients. At 1st relapse, 20 patients received pentostatin of whom 17 had previously received this agent, and 53 patients received cladribine of whom 44 were previously treated with pentostatin. Patients relapsing after an initial CR showed no significant difference in ability to re-attain CR as opposed to PR or no response, whether retreated with the same agent, or switched to the other. However, for patients who initially failed to achieve CR, switching to the alternative agent was associated with an increased rate of CR although this difference did not achieve statistical significance. Known 2nd malignancies (excluding basal cell carcinoma) occurred in 20 patients (9 %). In a separate group of 7 patients who were never treated with either agent, 2 patients developed 2nd malignancies. We demonstrated equivalent efficacies of pentostatin and cladribine in the treatment of HCL. Median survival has not been reached for either agent. At 10 years FU, the survival is 83% (pentostatin) and 90% (cladribine). DFS curves show no plateau for either agent with relapses occurring up to 16 years after pentostatin treatment. True cure in this disease thus remains elusive, however, our results suggest that first line CR with purine analogue therapy should be the prime aim of HCL treatment.

Acute Myeloid Leukemia Following Treatment with Cladribine for Hairy Cell Leukemia: A Case Report and Review of the Literature

The overall survival of patients with hairy cell leukemia (HCL) has significantly increased in recent years because of the development of effective treatments such as interferon alpha and purine analogs. Several reports have described an increased risk of secondary cancers, particularly solid tumors, in patients with HCL. We describe a case of a patient with HCL, who had prolonged pancytopenia after a single course of cladribine. Fifteen months after the diagnosis of HCL the patient developed acute myeloid leukemia (AML) and died shortly afterwards. Review of the literature shows few reports of acute leukemia in HCL patients. All of the 11 reported cases of leukemia in patients with HCL have been in patients who have been treated with either interferon alpha or purine analogs, and developed several years (mean 4.3 years; range 1.6-6.4 years) after the diagnosis of HCL. Our case is unusual in that the patient developed AML shortly (1.2 years) after the diagnosis and treatment of HCL. Further studies are needed to clarify whether leukemias seen in patients following the treatment of their HCL are incidental findings or related to HCL and its treatments.

Epstein – Barr Virus Positive Large B-Cell Lymphoma Arising in a Patient Previously Treated with Cladribine for Hairy Cell Leukemia

We describe the case of a patient treated with 2-chloro-2'-deoxyadenosine, CdA or Cladribine for hairy cell leukemia who subsequently developed an Epstein Barr virus (EBV)-positive polymorphous large B-cell lymphoma (p-LBCL). The time interval between Cladribine therapy and development of p-BCL was 11 months and morphologically resembled an EBV-positive post transplant lymphoproliferative disorder (PTLD). Molecular genetic studies for EBV-clonality by Southern blot hybridization showed a clonal population of infected cells, implying that this was an EBV induced lesion. The chronology of events suggest that Cladribine, a purine analog which has been previously described to induce long-lasting immunodeficiency, can, in some cases, weaken the host defense mechanism to a level at which an innocuous EBV infection may transform the normal lymphoid cells into an aggressive neoplasm. Unlike most methotrexate-related lymphoproliferative disorders (LPDs), which undergo spontaneous remission after discontinuation of therapy, LPDs secondary to purine analogs often fails to resolve after discontinuation of therapy and requires additional therapy. Our patient was treated with rituximab following the diagnosis of p-LBCL, with the goal of improving the pancytopenia to permit chemotherapy. However, the patient failed to show any dramatic improvements in counts, developed systemic symptoms and progressive ascites. He expired 3 weeks after a second dose of rituximab. Cladribine is a potent immunosuppressive agent and should be included with the list of immunosuppressive agents that may be associated with EBV-related B-cell lymphoproliferative disorders.

Epstein-Barr Virus Positive Large B-Cell Lymphoma Arising in a Patient Previously Treated With Cladribine for Hairy Cell Leukemia

Epstein-Barr Virus Positive Large B-Cell Lymphoma Arising in a Patient Previously Treated With Cladribine for Hairy Cell Leukemia