Adverse event rates and economic burden associated with purine nucleoside analogs in patients with hairy cell leukemia: a US population-retrospective claims analysis

Background: Purine nucleoside analogs (PNAs) are highly effective for first-line treatment of hairy cell leukemia (HCL). In clinical trials of single PNAs, several adverse events (AEs) were reported; however, little is known regarding the costs and healthcare resource utilization (HRU) resulting from AEs in HCL patients (pts) treated with PNAs in non-clinical trial settings. Objective: Determine the costs and HRU of high incident and clinically important AEs associated with PNA therapy in HCL pts in the Truven MarketScan database. Methods: Adults (aged ≥18 years) with ≥2 HCL diagnosis codes ≥30 days apart during January 1, 2006–December 31, 2015 were included. Pts had ≥1 prescription claim for a PNA (cladribine or pentostatin ± rituximab) after HCL diagnosis date. First PNA claim date was defined as the index date. Pts had continuous health plan enrollment for ≥6 months at baseline and ≥12-months follow-up with no PNA in the baseline period. Pts were placed into cohorts based on the occurrence of myelosuppression (MSPN) and opportunistic infections (OI) as these were highest incident and clinically important AEs observed. Generalized linear models were used to compare outcomes during the 12-month follow-up. Results: Of the 219 pts with no history of MSPN, 101 developed MSPN (incidence [I]: 461 per 1000 pt-years) and of 619 pts with no history of OI, 26 developed OI (I: 42 per 1000 pt-years). Demographics were similar between pts with and without MSPN and OI. Pts who developed OI or MSPN had significantly higher inpatient admissions and costs (Table 1). Conclusions: PNA-treated HCL pts who developed MSPN or OI incurred higher HRU than those who did not develop either condition. This indicates the need for new therapeutic strategies to reduce HCL-treatment-associated toxicities.

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A Unique Hairy Cell Leukemia Variant

Case Reports in Oncology ◽

10.1159/000446696 ◽

2016 ◽

Vol 9 (2) ◽

pp. 312-316

Author(s):

Charles Jian ◽

Cyrus C. Hsia

Keyword(s):

Flow Cytometry ◽

B Cell ◽

Hairy Cell Leukemia ◽

Nucleoside Analogs ◽

B Cell Lymphoma ◽

Purine Nucleoside ◽

Peripheral Blood Flow ◽

Hairy Cell ◽

Cell Leukemia ◽

Normal Peripheral Blood

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.

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Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial

Journal of Hematology & Oncology ◽

10.1186/s13045-020-01004-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Robert J. Kreitman ◽

◽

Claire Dearden ◽

Pier Luigi Zinzani ◽

Julio Delgado ◽

...

Keyword(s):

Hairy Cell Leukemia ◽

Residual Disease ◽

Braf Inhibitor ◽

Nucleoside Analogs ◽

High Rate ◽

Hairy Cell ◽

Cell Leukemia ◽

Long Term Follow Up

Abstract Background Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL). Methods Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 purine nucleoside analogs (PNAs), or ≥ 1 PNA followed by rituximab or a BRAF inhibitor. Patients received 40 µg/kg moxetumomab pasudotox intravenously on Days 1, 3, and 5 of each 28-day cycle for up to six cycles. Disease response and minimal residual disease (MRD) status were determined by blinded independent central review. The primary endpoint was durable complete response (CR), defined as achieving CR with hematologic remission (HR, blood counts for CR) lasting > 180 days. Results Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26–48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3–4 events; these events were generally reversible. No treatment-related deaths were reported. Conclusions Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy. Trial registration ClinicalTrials.gov identifier: NCT01829711; first submitted: April 9, 2013. https://clinicaltrials.gov/ct2/show/NCT01829711

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Infection at the Time of Initial Therapy for Hairy Cell Leukemia Is Associated with Inferior Time to Next Treatment

Blood ◽

10.1182/blood-2018-99-119951 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2305-2305 ◽

Cited By ~ 1

Author(s):

Narendranath Epperla ◽

Mirela Anghelina ◽

Qiuhong Zhao ◽

Akwasi Agyeman ◽

James S. Blachly ◽

...

Keyword(s):

Hairy Cell Leukemia ◽

Research Funding ◽

Nucleoside Analogs ◽

Small Sample ◽

Hairy Cell ◽

Cell Leukemia ◽

Infection Group ◽

Increased Risk ◽

Significant Difference ◽

The Impact

Abstract Introduction: Hairy Cell Leukemia (HCL) is a rare, chronic hematological malignancy that makes up approximately 2% of all leukemias. HCL patients are at a markedly increased risk for infection related to a combination of disease-related and treatment-related immunosuppression which has been well described in the literature. However, the significance of infection prior to initiation of HCL therapy and its impact on the subsequent selection of HCL treatment, or outcomes, is not well described. Using the HCL patient data registry, we report here the impact of antecedent infection on the treatment patterns and outcomes of HCL patients. Methods: We evaluated adult (≥18 years) patients with HCL who had information regarding antecedent infections and subsequent HCL treatment during 1984-2018. The primary endpoint was progression-free survival (PFS-1). Secondary endpoint included time to next treatment (TTNT). PFS-1 was measured from the date of first HCL treatment to date of progression/death or last follow-up. TTNT was defined as the time from first HCL treatment to initiation of second HCL treatment. The study population was stratified into 3 groups based on the presence or absence of antecedent infections: no infection prior to first HCL treatment (no infection group), infection within 30 days prior to first HCL treatment (infection1 group) and infection >30 days prior to first HCL treatment (infection2 group). Fisher's exact test or Kruskal-Wallis test was used to compare the characteristics among the no infection and infection groups and the Cox proportional hazard model was used to evaluate the association with PFS-1 and TTNT. Results: A total of 205 HCL patients who had information regarding antecedent infections and subsequent HCL treatment were eligible for the study. Among these, 144 (70%) belonged to the no infection group, while 26 patients (13%) belonged to infection1 group and 35 (17%) to infection2 group. Patient characteristics are shown in Table 1 with a breakdown between the three groups. The majority of the patients were Caucasian with a male preponderance and had classic HCL. The patients in the infection1 group had a lower median WBC (K/uL) (1.9 vs 3.1 vs 2.9), particularly the absolute neutrophil count (K/uL) (0.4 vs 0.7 vs 0.8) and significantly lower median hemoglobin (gm%) (10.1 vs 12.2 vs 12.4) relative to the no infection and infection2 groups, respectively (p=0.01). Similarly, a greater proportion of patients in the infection1 group had significant comorbidities (including pulmonary, gastrointestinal and hepatic disease) relative to no infection and infection2 groups as shown in Table 1. The majority of patients received purine nucleoside analogs as their first HCL treatment (no infection group=92%, infection1 group=85%, infection2 group=94%). The median PFS-1 (in years) was better in the no infection group compared to the infection1 group but was not statistically significant (17.0 [95% CI=7.9-not reached (NR)] vs 8.8 [95% CI=4.2-NR], respectively, p=0.98, Figure 1). However, the median TTNT (in years) was significantly longer for HCL patients with no infection versus the infection1 group (6.3 [95% CI=5.4-7.8] vs 3.6 [95% CI=0.7-NR], respectively, p=0.001, Figure 1). On subgroup analysis, relative to the no infection group, median PFS-1 (in years) was not significantly different in infection1 group treated with Pentostatin (10.7 [95% CI=3.53-NR] vs NR [95% CI=1.38-NR], respectively, p=0.43), however, the median PFS-1 (in years) was shorter in the infection1 group treated with Cladribine (17.0 [95% CI=7.67-NR] vs 4.0 [95% CI=2.00-NR], respectively), although not reaching statistical significance (p=0.09) probably due to small sample size. Conclusion: In this large series of HCL patients who received treatment, we show that the patients who had infections at the time of HCL treatment have a significantly shorter TTNT. The reasons for this are unclear but may indicate that patients were unable to receive treatment in a timely manner because of the infection, or were unable to complete treatment because of complications. The significant difference in hemoglobin between the infection1 and other groups indicates the possibility that these patients had more advanced HCL at the time of diagnosis. These findings indicate the potential long term negative impact of infections in patients who need treatment for HCL and reinforce the need for careful management in this setting. Disclosures Lozanski: Beckman: Research Funding; Coulter: Research Funding; Stem Line: Research Funding; Genentech: Research Funding; Novartis: Research Funding; BI: Research Funding. Andritsos:HCLF: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy.

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Long Term Follow-Up of Patients with Hairy Cell Leukemia (HCL).

Blood ◽

10.1182/blood.v104.11.3473.3473 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3473-3473 ◽

Cited By ~ 3

Author(s):

Farhad Ravandi-Kashani ◽

Hagop Kantarjian ◽

Stefan Faderl ◽

Susan O’Brien ◽

Deborah Thomas ◽

...

Keyword(s):

Hairy Cell Leukemia ◽

Nucleoside Analogs ◽

Time Of Death ◽

Hairy Cell ◽

Cell Leukemia ◽

Term Outcome ◽

Long Term Outcome ◽

Long Term Follow Up

Interferon-a (IFN-a) and, more recently, nucleoside analogs (NA) such as 2-CDA and pentostatin have been used with significant success to treat HCL. A single course of 2-CDA produces response rates over 75%, with responses maintained for 4 years in 75% of pts. Similar results have been observed with pentostatin. (Dearden et al, Br J Haematol1999;106:515). To learn more about long-term outcome, we reviewed 234 pts with untreated HCL seen at the MDACC over a 30-year period; their median follow-up was 122 months from diagnosis (up to 387 months). Their median age at diagnosis was 50 years (range 23–83 years). Survival was superior among the 173 pts given either 2-CDA (n = 161) or pentostatin (n = 12) compared to those never given either NA (p = 0.042). Figure Figure Relapse occurred in 32 of 176 pts who received 2-CDA as their first chemotherapy either at MDACC or before presenting to MDACC. Therapy for relapse after 2-CDA included rituximab (N=9), a second course of 2-CDA (n=9), a second course of 2-CDA followed by rituximab (n=8), and other (n=6). No statistically significant differences in survival were seen possibly due to small pt numbers. The estimated 10-year and 20-year survival (from diagnosis) for the 176 pts who received 2-CDA as first chemotherapy was 84%, and 65%, respectively. Figure Figure The majority of pts who died were not in remission at time of death and thus presumably died of HCL. Hence alternatives to NA are needed in at least some pts, and we are evaluating whether covariates exist that might distinguish pts who do and do not relapse and, among the former, pts whose remissions are short. Pending identification of the latter and keeping in mind the length of the average remission, alternatives to NA should have very little toxicity. We have begun to add rituximab to 2-CDA to lengthen remission duration and thus extend survival in pts with untreated HCL.

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Modern Strategies for Hairy Cell Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2010.31.7016 ◽

2011 ◽

Vol 29 (5) ◽

pp. 583-590 ◽

Cited By ~ 24

Author(s):

Michael R. Grever ◽

Gerard Lozanski

Keyword(s):

Minimal Residual Disease ◽

Hairy Cell Leukemia ◽

Residual Disease ◽

Disease Free Survival ◽

Nucleoside Analogs ◽

High Rate ◽

Leukemic Cells ◽

Hairy Cell ◽

Cell Leukemia ◽

Minimal Residual

Enormous progress in the treatment of hairy cell leukemia over the last five decades has emerged as a result of organized clinical investigations. Although interferon represented one of the initial major therapeutic advances in the management of this disease in 1984, the subsequent introduction of purine nucleoside analogs (pentostatin and cladribine) changed the natural history of this rare disease by achieving a high rate of complete and durable remissions. The disease-free survival after effective therapy has not reached a plateau, suggesting control but not cure of the disease. Identification of minimal residual disease in patients achieving a complete hematologic remission provides insight into the potential source for predicting eventual relapse. Modern strategies of targeted therapies directed against immunophenotypic markers on the leukemic cells provide hope that improved long-term control of the disease is possible. Combined chemoimmunotherapy may hold the highest promise for disease eradication, but the optimal strategy for using this approach is under active investigation. Despite the perception by hematologists that this disease has already been conquered, there are critically important unanswered questions that remain. Investigation of the bone marrow microenvironment and its impact on minimal residual disease may ultimately prevent relapse. Consideration of the median age of patients at diagnosis combined with a substantial relapse rate mandates continued pursuit of improved therapy. The ultimate goal will be to achieve cure rather than simple control of the disease.

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Eradication of minimal residual disease in hairy cell leukemia

Blood ◽

10.1182/blood-2005-11-4590 ◽

2006 ◽

Vol 107 (12) ◽

pp. 4658-4662 ◽

Cited By ~ 97

Author(s):

Farhad Ravandi ◽

Jeffrey L. Jorgensen ◽

Susan M. O'Brien ◽

Srdan Verstovsek ◽

Charles A. Koller ◽

...

Keyword(s):

Minimal Residual Disease ◽

Hairy Cell Leukemia ◽

Residual Disease ◽

Disease Free Survival ◽

Nucleoside Analogs ◽

Hairy Cell ◽

Cell Leukemia ◽

Consensus Primer ◽

Number Of Patients ◽

Minimal Residual

AbstractAlthough the nucleoside analogs cladribine and pentostatin produce high response rates in patients with hairy cell leukemia (HCL), a significant number of patients eventually relapse. Several studies have demonstrated that patients with complete remission (CR) have a longer disease-free survival. Therefore, strategies to improve on the initial response to nucleoside analog therapy are likely to be beneficial, at least for a proportion of patients. We have treated 13 patients with newly diagnosed HCL (n = 11) or after failure of one prior chemotherapy (n = 2) with cladribine (5.6 mg/m2 given intravenously over 2 hours daily for 5 days) followed by 8 weekly doses of rituximab (375 mg/m2). All patients achieved a CR and minimal residual disease (MRD) assessed by consensus primer polymerase chain reaction (PCR) or flow cytometry was eradicated in 11 (92%) of 12 and in 12 (92%) of 13 of patients, respectively. There was no decline in the absolute CD4 and CD8 lymphocyte number after rituximab. We conclude that eradication of MRD in HCL is possible. Whether this leads to a reduced risk of relapse would need to be evaluated in a larger number of patients and with longer follow-up. Disease characteristics may potentially be used to identify patients that are more likely to benefit from such additional therapy.

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How I treat hairy cell leukemia

Blood ◽

10.1182/blood-2009-06-195370 ◽

2010 ◽

Vol 115 (1) ◽

pp. 21-28 ◽

Cited By ~ 97

Author(s):

Michael R. Grever

Keyword(s):

Hairy Cell Leukemia ◽

Residual Disease ◽

Disease Free Survival ◽

Nucleoside Analogs ◽

Leukemic Cells ◽

Hairy Cell ◽

Cell Leukemia ◽

Patient Responses ◽

Classic Form

Abstract The description of hairy cell leukemia as a specific clinical entity was published 50 years ago. The clinical outcome for patients was hampered by ineffective chemotherapy, and splenectomy was the major therapeutic approach to improve peripheral blood counts. The median survival after diagnosis was 4 years. With the introduction of α-interferon in 1984, marked improvements in patient responses were observed. Shortly thereafter, the introduction of the purine nucleoside analogs transformed this disease into a highly treatable form of leukemia, and patients with the classic form of this rare leukemia now have a near-normal life expectancy. However, other clinical entities mimicking this disease do not respond; thus, accurate diagnosis is important. Immunophenotypic features in classic hairy cell leukemia show that the leukemic cells express CD11c, CD25, CD103, and CD123 and display bright CD20. Despite the high percentage of durable complete remissions with modern therapy, the long-term disease-free survival curves have not reached a plateau. Many patients who achieve a complete remission by morphologic criteria have minimal residual disease demonstrable by either flow cytometry or immunohistochemical staining, and this population may be at higher risk for earlier relapse. Continued clinical research is essential to optimize therapy for this disease.

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