What is Hairy Cell Leukemia: Clinical Course & Treatment

Michael Grever
The Ohio State University

Hairy cell leukemia is a chronic and relatively rare form of adult leukemia. It is estimated that approximately 2 % of all adult patients with leukemia have this form of disease. While the cause of this malignancy is not known, the origin of the malignant cell is thought to develop from the memory B cell compartment. These malignant cells infiltrate the bone marrow, the spleen, and the liver from the time of diagnosis. In the spleen, there is a characteristic location of these leukemic cells in the splenic red pulp. While lymph nodes in the abdomen may be involved, lymph nodes are rarely enlarged on physical examination.

In 1958, Dr. Bertha Bouroncle and colleagues described 26 patients with this disease that she called “leukemic reticuloendotheliosis”. In this original description of a large series of patients, she identified the clinical presentation and features of this disease. Thus, this entity was recognized as a separate form of leukemia and was characterized by monotonous cells with a serrated border. The leukemic cells were present in the peripheral blood and had projections emanating from the cytoplasmic border. Ultimately, this disease was called “hairy cell leukemia”.

While unexplained, this disease has a male predominance with a ratio of 4:1 men to women with a median age at diagnosis of 52 years. There is a wide range of ages for patients with this disease. The main presenting symptoms include fatigue or weakness. Infection may also be quite prominent as a result of neutropenia and monocytopenia. Patients may present with bacterial or opportunistic infections. Patients may complain of early satiety as a result of an enlarged spleen. Finally, there are an increasing number of patients who are without symptoms, and present for diagnosis because of an abnormal screening blood count or physical examination. Consequently, it is typical for patients to be referred for evaluation of some combination of anemia, neutropenia, thrombocytopenia, and splenomegaly.

Before 1984, the treatment of this disease was unsatisfactory. Available chemotherapy included alkylating agents that often caused worsening of blood counts. In general, patients were often referred for splenectomy that temporarily improved the low blood counts. While other therapy was also attempted, the median survival was approximately 4 to 4.5 years in patients who were treated with removal of the spleen. Responses to alpha-interferon were first published by MD Anderson Hospital in 1984. Subsequently, other investigators confirmed the benefit of interferon. Marked improvement in blood counts meeting the definition of response were observed in about 80% of patients with 10% achieving complete remissions. In the same year 1984, a report by Spiers and colleagues indicated that complete remissions were also observed in a small cohort of patients with hairy cell leukemia who were treated with pentostatin.

Subsequently, pentostatin was reported by other groups to secure a complete remission in 75 to 90% of patients who were previously untreated. In 1990, the first report of cladribine administered by a seven-day intravenous infusion showed a complete remission in 11 out of 12 patients. While patients with an active infection were not included in these trials, the extraordinary high complete remission rate following a single course of therapy was reproduced in a large series of patients by the investigators at Scripps Clinic. Other investigators using alternative schedules of cladribine found complete remissions in 76 to 81% of patients.

Long-term follow-up studies on patients treated with either pentostatin or cladribine have shown that about 60% of patients remain in remission at 10 years of follow-up. In the approximate 40% of patients who relapse, there is a high chance of achieving a second remission. Second complete remissions with both purine agents have been reported to achieve complete remissions ranging from 52 to 75% of patients.. As a result of these remarkable results, the natural history of patients with this disease has been substantially improved with the use of these purine agents. Patients with hairy cell leukemia have a near normal life expectancy compared to the much poorer results of three decades ago.

Hairy Cell Leukemia -- Can this disease be cured?

Kanti R. Rai, Matthew Kaufman, Mark Hoffman
Albert Einstein College of Medicine

Can this disease be cured? We will try to answer this question from two separate perspectives:

A. From the perspective of a patient who has been diagnosed to have hairy cell leukemia (HCL), the question whether this disease can be cured is most pertinent. Before we provide a yes or no answer, it is important to provide a relevant background.

HCL is a relatively rare disease and until the mid 1980s, the treatment approaches were aimed at palliation of symptoms. Some patients either had splenectomy and many of whom went on to live a symptom-free and good quality life for a decade or more. Some patients required chemotherapy, which mostly consisted of orally administered chlorambucil which perhaps provided relief in symptoms, but the natural history of the disease was unaffected. Finally, some patients lived a relatively full-life, free of symptoms and without ever requiring any treatment at all. During that era, the disease, unquestionably, was incurable.

During the 1980’s however, there was a flicker of hope for patients with HCL when therapy with alpha-interferon was introduced. However, despite our initial promise with interferon therapy because many patients with significant amount of disease had objectively measurable benefits; the overall disease course was slowed, but by no means was it controlled for prolonged periods. The disease still was considered incurable.

Late 1980’s and early 1990’s witnessed a dramatic improvement in the long-term outlook for HCL patients with the emergence, first of pentostatin, which was quickly followed by a second nucleoside-analog-group of chemotherapy drugs, cladribine. Both of these drugs quickly demonstrated, for the first time, that HCL patients could now expect to achieve a complete remission (CR) of their disease with acceptable and short-lasting toxicities. These CRs proved to be of long duration. No longer were there any non-believers in the claim that cladribine and pentostatin treatments resulted in prolongation of life-expectancy (with good quality life) of HCL patients.

With the experience gained wold-wide with a large number of patients with HCL treated with cladribine or pentostatin and with 80% to 90% having achieved a CR and followed for up to two decades, two facts have been recognized.

1. Virtually all the long-term survivors who continue to remain in “clinical” CR throughout these 10 or 15 years of follow-up, carry evidence of minimal residual disease (MRD) by any of the following criteria: (i) two or four color flow cytometry (CD11c and CD22 co-expression, or positivity for CD103 and CD25), (ii) clonal expression of sIg light chains on CD22 positive cells, (iii) by polymerase chain reaction (PCR) method.2

2. Thus, from a purist’s perspective, we can not claim a total victory over hairy cell leukemia. There is no question, however, that today, HCL patients live longer and are in CR but most of them have persisting evidence of MRD. Unfortunately they all remain at risk of suffering a clinical relapse and possibly may need retreatment.

B. From the perspective, however, of a scientific approach, the very fact that many long-term survivors of HCL, who are continuing to remain in CR by clinical criteria, still have persisting evidence of minimal residual disease, are at risk for relapse, is a challenge. Some among us (the scientists or clinical investigators) would like to give HCL patients the hope for a cure, i.e. elimination of MRD, so that we can expect that the danger of relapse has finally been eliminated.

Based on the above renewed interest in basic science research has to be developed. The sense of complacence that now prevails among clinicians and patients should be replaced by the sobering truth that although a significant progress has been made, the fight is far from over. We must return to the laboratory bench and try to understand why a small number of hairy cells manage to survive while the large majority of them have been successfully eliminated. We also must keep in mind that in our enthusiasm to try to kill those last remaining hairy cells, we do not cause unacceptable levels of toxicities and thus end-up with a patient who might not have any evidence of residual hairy cell leukemia, but now is left with compromised quality of life because of toxicities resulting from these additional treatments. It is in the context of this challenge that the recently opened door to try to use the anti-CD20 monoclonal antibody rituximab after achieving a remission with pentostatin or cladribine seems to be an extremely attractive development. This approach is relatively free of undue toxicities and is worthy of a properly planned, and perhaps randomized clinical trial with companion laboratory-based correlative sciences studies.

Thus, in our opinion, the answer to the originally posed question is: Yes! This disease can be cured. It will require a concerted collaborative study with participation with all the experts in HCL spread all over the western hemisphere.

Approach to the Patient after Relapse of Hairy Cell Leukemia

Robert Kreitman, MD
National Institutes of Health

Need for additional therapies.

The results of therapy with purine analogs cladribine and pentostatin for hairy cell leukemia are excellent, with 85-95% of patients achieving complete remission (CR), only about 40% of patients relapsing by 10 years [1-3], and 75% achieving 2nd CR [1]. However, disease-free survival curves fail to show a plateau even after 10 years, and hence there is no evidence of cure. Moreover, while 3rd and 4th CRs are common with repeated courses of purine analogs, the CR rates decline significantly with each successive course, whether the same purine analog is used or not [4,5]. Because a single course of cladribine or pentostatin is reported to suppress CD4+ lymphocytes below the lower limit of normal for a median of 40 or 54 months, respectively [6,7], it may be unsafe to use repeated courses of purine analogs to maintain HCL patients, particularly at short intervals. The use of rituximab, while not approved for HCL, is an important advance because this anti-CD20 monoclonal antibody (MAb) spares T-lymphocytes. CR rates among the 6 reported rituximab studies in HCL (10-25 patients each, total 97) vary from 10 to 54% [8-13], However, in the 51 patients from 5 studies who demonstrated a need for treatment based on cytopenias and who had at least 1 prior purine analog, there were 10 (20%) CRs and 10 (20%) PRs [8-12]. In the largest single trial enrolling 24 such patients, there were 3 (13%) CRs and 3 (13%) PRs [10]. Thus, new treatments are needed for relapsed HCL which have both high efficacy and lack of cumulative toxicity, particularly to T-cells. Recombinant immunotoxins are currently being developed to meet this need.

Recombinant immunotoxins.

Protein toxins are among the most potent natural substances known, in that they act catalytically and can therefore kill a cell with a single molecule in its cytoplasm [14]. Plant toxins inactivate ribosomes by preventing their association with elongation factor-1 and -2 (EF-1 and EF-2). Bacterial toxins such as Pseudomonas exotoxin (PE) and diphtheria toxin (DT) ADP-ribosylate EF-2, leading to protein synthesis inhibition in either case, which induces cell death by apoptosis [15,16]. Bacterial toxins, which are more often used to fuse to ligands, are naturally made by bacteria in single-chain form, composed of domains for binding and ADP-ribosylation at opposite ends, and a translocation domain in between [16-19]. The orientation of the domains are opposite in PE and DT, with the binding domain at the amino terminus of PE and at the carboxyl terminus of DT. They intoxicate cells by binding to the cell surface, undergoing internalization, unfolding within an acidic vesicle, undergoing proteolytic cleavage within the translocating domain, and translocating to the cytosol where EF-2 is inactivated by ADP-ribosylation [19]. Recombinant toxins are produced by replacing the binding domain with a cancer cell-binding ligand. In denileukin diftitox, approved for relapsed and refractory cutaneous T-cell lymphoma, human interleukin-2 replaces the binding domain of DT at the carboxyl terminus [20-22]. In recombinant immunotoxins, the cell-binding ligand is an Fv fragment, a recombinant antibody containing the variable domains of a Mab [23]. In the recombinant immunotoxin LMB-2, the variable domains of the anti-CD25 Mab are fused together by a peptide linker and then fused to the amino terminus of PE38, a fragment of PE which is missing its binding domain [19,24]. In the recombinant immunotoxin BL22, the variable domains of the MAb RFB4 are fused to PE38, but the Fv is stabilized with an engineered disulfide bond rather than a peptide linker [25-27].

LMB-2 targeting CD25.

LMB-2 was the first recombinant immunotoxin reported to be of benefit for HCL, with 4 (100%) responses out of 4 patients treated as part of a phase I trial, one of whom had a durable CR [28,29]. The 3 patients with PR had inadequate treatment due to pneumonia, dose-limiting toxicity (DLT) and immunogenicity, suggesting that significant clinical activity might be observed in a phase II setting. Unlike purine analogs, myelosuppression and severe lymphopenia were not observed with LMB-2 [28,29], which was expected since normal T and B-cells have insufficient CD25 expression to be sensitive [30,31]. The most common toxicities of LMB-2 included non-dose limiting hypoalbuminemia, transaminase and alkaline phosphatase elevations, and fever. A disadvantage of targeting CD25 in HCL is that 10% of patients have a variant (HCLv) in which CD25 is absent [32,33], and this variant is over-represented by patients with relapsed/refractory disease after purine analogs. Both HCLv and classic HCL uniformly express high levels of CD22, and have more recently been targeted by the recombinant immunotoxins BL22.

BL22 targeting CD22.

In phase I testing, 31 of the 46 patients had HCL relapsed or refractory after purine analogs, and of these 31 patients there were 19 (61%) CRs and 6 (19%) PRs [34,35]. A completely reversible form of hemolytic uremic syndrome (HUS) was observed in 4 (13%) of patients, but only during retreatment with a 2nd or 3rd cycle. However, most (58%) of the CRs were achieved with 1 cycle, suggesting that retreatment was not always necessary or advisable. Therefore, in the phase II trial, patients were observed without retreatment if they achieved CR or at least the CBC values required for CR, and if not, they were retreated at a lower dose level. One cycle of BL22 induced CR in 25% of 36 patients, and by retreating the 56% of patients who were eligible for retreatment, the CR rate rose to 47%, with an overall response rate of 72% [36]. Compared to the phase I trial, the dose-limiting HUS rate was less than half (6 vs 13%) and the immunogenicity rate less than one-third (11 vs 35%). The median CR duration was 5-46+ (median 22+) months, with 76% of 17 CRs ongoing [36]. Response was not significantly related to length of prior purine analog response, but was significantly higher in patients with spleens < 200 mm in maximal dimension than in patients with either larger spleens or prior splenectomy. Pharmacokinetic studies showed significant inverse relationships between area under the curve (AUC) and tumor burden measured by either the log of the HCL count in the blood, or the spleen size. It was concluded that BL22 is highly active in HCL despite prior purine analog treatment and resistance, and that experimental therapy should be considered in patients prior to removing the spleen or allowing it to become massive in size.

HA22, a high affinity mutant of BL22.

Patients with chronic lymphocytic leukemia (CLL) were not as sensitive to BL22, attributed to much lower expression of CD22 on CLL compared to HCL cells [35]. To allow a higher percentage of bound immunotoxin to be internalized by CD22 rather than disassociating from this antigen, the off-rate of BL22 was lowered by mutagenesis within the 3rd complementarity determining region of the heavy chain. The resulting anti-CD22 recombinant immunotoxin HA22 contained 3 amino acid mutations and bound with 15-fold higher affinity and lower off-rate to CD22, and had improved cytotoxicity [37-39]. HA22 is undergoing phase I testing in HCL, CLL and non-Hodgkin’s lymphoma (NHL). The HCL trial is associated with a response rate similar to that of BL22, but without dose limiting HUS at this time.

Approach to patients with relapsed HCL.

Many different treatment approaches to the relapsed patient exist, and lack of randomized data prevents discounting most of them as inappropriate. A list of common standard therapies is shown in Table I, together with some (but not all) appropriate situations for their use. Because of the long-term immunosuppression of purine analogs and their decreased efficacy with retreatment, a general strategy has been to avoid multiple courses of these agents with short time intervals in between. After first relapse with first purine analog response duration less than 12-24 months, or after multiple relapses from purine analog, salvage treatment with rituximab or experimental treatment with LMB-2, BL22 or HA22 has been successful [28,29,35,36,40-43]. Combined treatment with both purine analog and rituximab has been successfully employed in both the 1st line and relapsed setting [5,44-47]. This approach is attractive because rituximab may lengthen the response duration of purine analog without adding long-term immunosuppression, and delay the eventual use of repeat courses of purine analog. Interferon is clearly inferior to purine analog for achievement of response [48], but its relative lack of immunosuppression may offer palliation or delay in more toxin therapy [49]. Finally, splenectomy should be avoided in patients contemplating recombinant immunotoxin experimental treatment [36], but should always be considered in patients with even mild or moderate splenomegaly who have exhausted other options and risk fatal complications of the disease [49,50].

Prevention of relapse by combining rituximab with cladribine.

One way to address relapsed HCL is to prevent or delay relapse by eliminating the minimal residual disease (MRD) leftover after CR to cladribine. A preliminary report shows excellent activity of rituximab in eliminating MRD when used 4 weeks after cladribine in 13 patients [44]. This trial was not designed to determine whether rituximab should be used during 1st or 2nd line cladribine because comparison with cladribine alone was not done. To determine the benefit of adding rituximab to first or 2nd line cladribine, a randomized study is underway at the National Cancer Institute which also allows patients to be treated by their local physicians. Patients with 0 or 1 prior course of cladribine are randomized separately. Within each of these stratifications, half of the patients receive rituximab beginning with the 1st dose of cladribine, half receive cladribine without rituximab, and all patients receive delayed rituximab at least 6 months later if MRD can be demonstrated in the blood. Thus the 1st goal is to determine if rituximab can decrease the rate of MRD observed in the blood at 6 months, the time point at which patients generally achieve their minimum disease burden after cladribine [51,52]. The 2nd goal is to determine if MRD-free survival is better if rituximab is used up front or delayed. It is quite possible that rituximab may work better if delayed at least 6 months after cladribine when disease is minimal and clumps of cells are more permeable to rituximab. Alternatively, rituximab may work synergistically with cladribine and have optimal activity up front. Regardless of when the rituximab is added in combination with cladribine, we believe that patients with HCL may benefit from combined treatment and should be referred for the randomized and non-randomized trials of cladribine and rituximab if possible.

Complications of Treatment of Hairy Cell Leukemia

Martin S. Tallman, MD
Aaron Polliack, MD
Northwestern University

Standard treatment for patients with hairy cell leukemia (HCL) now includes a purine analog, either 2-chlorodeoxyadenosine (2-CdA, Cladrabine) or 2-deoxycoformycin (2-DCF, Pentostatin). In general, either purine analog is quite well tolerated and both induce high rates of complete remission and prolonged remission duration. Importantly, the typical toxicities of conventional cytotoxic chemotherapy including, nausea, emesis, alopecia and many other constitutional symptoms are generally not observed. The two most important toxicities observed with either purine analog include fever and immunosuppression. Fever often occurs often between day 5 and day 8 of the 7-day continuous infusion schedule of 2-CdA. Blood cultures are rarely positive. Patients who developed fever above 100.5-101 routinely are cultured and placed on broad-spectrum (usually oral) antibiotics until the fever resolves and cultures are demonstrated to be sterile. Non-steroidal anti-anflammatory drugs (Naprosyn, for example), if the platelet count permits, can be administered and usually results in resolution of the fever.

Prophylactic myeloid growth factors may shorten the duration of neutropenia, but have not been shown to be of major benefit with respect to other endpoints such as number of febrile days or frequency of admission for antibiotics and are generally not recommended. The presence of fever which is often coincident with decline in the number of circulating hairy cells, is believed to be likely related to lysis of hairy cells with release of cytokines. Immunosuppression may be quite prolonged, up to 1-2 years or even longer. Interestingly enough, the kinetics of lymphocyte subset recovery may explain the lack of frequent apparent infections. Regeneration of CD8-postive and NK positive cells is complete within three months where as CD20- positive and CD4-positive cells often require a prolonged period of recovery, often 1-2 years. Although infectious complications, including opportunistic infections, appear very uncommon, an occasional case of dermatomal herpes zoster infection has been reported. Infectious complications have been occasionally reported among patients treated with 2-DCF. While most are not life-threatening, initial studies reported pneumonia and herpes zoster infection most commonly. Despite measurable immunosuppression, opportunistic suppression are relatively uncommon.

Peripheral neuropathy has been reported with purine analogs, but not commonly with the doses of 2-CdA or 2-DCFadministered in patients with hairy cell leukemia. Other toxicities which have been reported include nausea and emesis (with 2-DCF), skin rash. Treatment with purine analogs has been occasionally associated with hypoplasia of the marrow despite apparent adequate hematopoietic recovery of the peripheral blood counts.

Experience in the Treatment of Hairy Cell Leukemia with Pentostatin and Cladribine

James Johnston, MD
CancerCare Manitoba

In 1983 we treated our first hairy cell leukemia (HCL) patient in Winnipeg, Manitoba, with pentostatin. The patient was a transfusion-dependent 45 year old man with progressive HCL following a splenectomy and a course of low-dose chlorambucil. The rationale for using pentostatin was based on the recent observations showing that chronic lymphocytic leukemia (CLL) was highly sensitive to this agent. Like CLL, HCL had recently been shown to also be a chronic B cell disorder. [1] Our patient received pentostatin 4 mg/m2 weekly intravenously, and after three treatments therapy was halted because of worsening anemia thought related to the drug. Over the ensuing weeks the blood counts normalized and by 8 weeks the patient had achieved a complete remission. Thereafter we started treating patients with a similar regimen using pentostatin 4 mg/m2 weekly x 3 (one cycle) with cycles repeated every 8 weeks. Patients had a marrow at the time of each cycle and once a complete remission was obtained they received two further cycles in an attempt to consolidate the remission. Of 28 patients treated with this regimen in a Canadian National Cancer Institute study, all responded with 90% achieving a complete remission. [2] A complete remission was obtained in one-third with once treatment cycle, one-third with two cycles and one-third with three cycles. At a median follow-up time of 10 years (55 to 133 months), half of the complete responders remained in complete remission. [3] The major toxicities were marrow suppression and infections with the initial cycle of treatment and nausea/vomiting.

For cost reasons, approximately 15 years ago we started using cladribine to treat HCL rather than pentostatin. Cladribine did not appear to cause nausea/vomiting but appeared to be more myelosuppressive. Initially, cladribine was administered by continuous infusion for 7 days, as recommended by Saven et al. [4] However, for simplicity we subsequently switched to cladribine 0.12 mg/k/day for 5 days, with each infusion administered over 2 hours. [5] We found that patients were exquisitely sensitive to this regimen but there could be further marrow suppression with the initiation of treatment and the risk of infections. The author thus presently uses weekly cladribine (0.15 mg/kg) intravenously for 6 treatments, as pioneered by Dr Lauria [6], only proceeding with each treatment as long as the blood counts have recovered to baseline and using filgrastim if there is delayed recovery. We have found this regimen to be well tolerated, highly effective and there have been no problems with infections.

Goal of Treatment

Darren Sigal, MD and Alan Saven, MD
Scripps Clinic Medical Group

Any decision to initiate treatment for hairy cell leukemia (HCL) must be accompanied by a clearly defined goal of treatment: what is the desired effect? HCL therapy has two key goals. First, treatment should correct the indication that necessitated treatment. Second, it should produce a durable remission that will delay additional therapy for prolonged periods of time. These two treatment goals are the same whether patients are newly diagnosed or have relapsed.

Indications for treating HCL patients are also the same, whether newly diagnosed or relapsed. They are anemia (hemoglobin <8-10 g/dL), thrombocytopenia (platelet count <50-100 X 10⁹/liter) or neutropenia (absolute neutrophil count <0.5-1X10⁹/liter). Less common indications are recurrent infections, symptomatic splenomegaly, bulky or painful lymphadenopathy, and leukocytosis with a high proportion of hairy cells (white blood cell count >20 X 10⁹/liter).

Purine analogues (both cladribine and pentostatin) produce very high rates of complete and overall responses. Saven and colleagues reported on 349 HCL patients treated with cladribine, the oldest and largest series of cladribine-treated HCL patients (Saven, Blood, 1998). All patients in this study satisfied the treatment criteria listed above. Despite half of these patients having received prior treatment, 98% achieved an overall response and 91% achieved a complete response after a single seven-day course of continuous infusion cladribine. Extended follow-up of patients in this study noted that remissions were maintained for over eight years (Goodman, J Clin Oncol, 2003). Other long-term studies confirmed that cladribine produced remissions that persisted for years (Else, J Clin Oncol, 2008; Chadha, Blood, 2005). A recent report could not identify hairy cells in patients who have been in a continuous complete remission having received cladribine therapy over 16 years previously (Sigal, ASCO abstract, 2008).

Remarkable response rates and very prolonged remissions should offer patients a profound sense of hope. However, HCL is still not considered a curable disease and “cure” should not be the goal of treatment. HCL has been detected in the bone marrows of patients treated 20 years earlier who have maintained perfectly normal blood counts and feel fine without any signs or symptoms of HCL. This reinforces the notion that treatment is only necessary for the specific indications listed above, and not for simply the mere presence of hairy cells. It also indicates that although a complete response is preferable, partial responses can also be very long-lasting.

The Role of Rituximab in Hairy Cell Leukemia

Deborah Thomas, MD
M D Anderson Cancer Center

Of all the leukemias, hairy cell leukemia (HCL) has the highest concentration of an antigen (expressed on the surface of the leukemia cell) designated as CD20. Rituximab is an agent given intravenously which attaches to the CD20 molecule with high specificity (in other words, it is a “monoclonal antibody”). When rituximab targets the CD20 molecule on the surface of the hairy cell, it starts a chain of events that ultimately leads to death of the leukemia cell (or lymphoma cell for that matter). Rituximab has been extensively tested in patients who have non-Hodgkin lymphoma (NHL), both the indolent (slow growing) and aggressive types. In NHL, rituximab has been active both as a single agent and in combination with standard chemotherapy. Rituximab has also been tested in patients with chronic lymphocytic leukemia (CLL), which has the lowest concentration of CD20 on the surface of the cell. When given as a single agent in previously treated CLL, it has a relatively low response rate because of the low levels of CD20 expression. When rituximab is given in higher doses or more frequently, the response rates improve somewhat. But when rituximab is given in combination with standard chemotherapy for newly diagnosed CLL, it nearly doubles the complete remission (CR) rate, meaning that it synergizes with the chemotherapy. This is a significant improvement in outcome.

When rituximab is given to patients who have received prior therapy for HCL, it is able to reduce or eradicate the disease in a significant proportion of patients (Table 1). Most of the studies performed to date used standard doses of rituximab for at least 4 weeks. Responses appear to be better when there is a lower burden of disease prior to the start of therapy. Rituximab is therefore a viable treatment option to give by itself in cases where chemotherapy may not be the optimal choice.

Table 1. Rituximab in relapsed/refractory hairy cell leukemia

No, number of patients; CR, complete remission; PR, partial remission; OR, overall response.
*Rituximab 375 mg/m2

Standard chemotherapy for HCL includes “nucleoside analogs” such as cladribine (2-CdA) or deoxycoformycin (pentostatin, DCF). These agents have been very effective at inducing long-lasting remissions, although the HCL can recur after several years. Studies are now underway combining rituximab with 2-CdA, usually in a sequential fashion (2-CDA given first, then the rituximab later). The data thus far suggests that rituximab given by itself is very effective at eradicating the minimal residual disease (MRD) that may be left behind after treatment with 2-CdA. There is conflicting data whether eliminating the MRD will prevent the HCL from recurring. Although the data from ongoing studies of rituximab after 2-CdA therapy is encouraging, it is too soon to tell whether the addition of rituximab will prolong the time to the next treatment (better known as leukemia-free or progression-free survival) or even prolong a patient’s life span (overall survival). [6],[7] Patients with HCL leukemia have to be followed for several years before the impact of a new treatment (such as the addition of rituximab) can be detected. In addition, although rituximab is generally well tolerated, there are side effects (as with every medication). Most of the side effects occur during the first infusion, such as fever and chills.

Based on the activity of rituximab and its usefulness in eradicating MRD, there are plans for a large clinical trial where patients will be randomized (as in a flip of the coin) to two different treatment schedules looking at how the rituximab and 2-CdA are combined. In addition, newer monoclonal antibodies against CD20 such as ofatumumab (which may be more potent than rituximab) will likely also be explored in patients with relapsed HCL.

The Scripps Clinic Cladribine Protocol

Darren Sigal, MD and Alan Saven, MD
Scripps Clinic Medical Group

Physicians at Scripps Clinic administer cladribine using the method first published in the New England Journal of Medicine in 1990 (Piro, N Engl J Med, 1990). The entire treatment consists of a single outpatient seven-day continuous infusion of cladribine at a dose of 0.1 mg/kg per day. The cladribine package insert recommends 0.085 mg/kg per day, the dose used for the first group of cladribine-treated HCL patients; this is related to the extinction coefficient of chloroadenine when cladribine was first synthesized at Scripps Clinic by Dr. Ernest Beutler (Beutler, Lancet, 1992). Patients have a peripherally inserted central catheter (PICC) placed by a specially trained nurse. A PICC line can remain in place for weeks and allows for outpatient continuous infusion. Patients have their PICC line connected to a chemotherapy pump that is loaded with the correct dose of cladribine. On the seventh day, the pump is disconnected and the PICC line can be removed. Patients have lab checks every two weeks until their blood counts recover.

Continuous infusion cladribine dosing was used in the first phase I study of cladribine and the first HCL cladribine study (Carson, Proc Natl Acad Sci, 1984; Piro, N Engl J Med, 1990). Pharmacokinetic properties of cladribine support this mode of administration (Liliemark, Cancer Res, 1991). Cladribine has also been given as a two-hour daily or weekly intravenous bolus or a daily subcutaneous injection (Juliusson, J Clin Oncol, 1995; Robak, Blood, 2007). These studies are smaller and with more limited follow-up. Most long-term follow-up studies have used continuous infusion dosing with impressive response rates and long-term remissions. Accordingly, Scripps Clinic physicians favor this approach. Most patients had normalization of their peripheral blood counts within seven weeks, first marked by normalization of platelet counts.

Cladribine produced fevers unrelated to infections in 42% of patients. The use of filgrastim (G-CSF) did not alter the rate of culture-negative fevers and is not recommended for routine use (Saven, Blood, 1999). Patients with neutropenic fever are not routinely given antibiotics unless associated with fever > 101 F, shaking chills, or an inability to maintain oral hydration despite acetaminophen. Rapid destruction of hairy cells and release of cytokines is thought to be responsible for the fevers. Hairy cells begin clearing form the peripheral blood within days, splenomegaly corrects within three months, and the bone marrow clears over six months. Tumor lysis syndrome can occur when large numbers of hairy cells are rapidly killed. However, allopurinol is generally not used because of the high rate of rash. Selected patients with a very large spleen or a large number of circulating hairy cells may be more appropriate to receive allopurinol.

Minimal Residual Disease

Martin S. Tallman, MD & Aaron Polliack, MD
Northwestern University

The remarkable activity of the purine anlogs in HCL has prompted the examination of bone marrow biopsies after treatment to detect minimal residual disease (MRD) in patients who appear otherwise in complete remission by routine morphology. Depending on the technique used (often anti-CD20 antibodies in paraffin-embedded biopsies specimen) and the criteria used, between 13-51% of patients in apparent complete remission by routine morpholgy has some evidence of MRD. While there is some evidence that MRD, as detected by immunohistochemistry, may predict relapse, it has not been shown that further treatment of patients who appear otherwise in apparent remission by routine morphology, but who have evidence of MRD by routine histochemistry have a better outcome than those who are observed. There is some evidence that the administration of Alemtuzamab (Campath-1H) after 2CdA can convert patients who have MRD to a molecularly negative state. However, whether this improves overall survival has not been demonstrated. Importantly, the presence in molecular studies using PCR techniques has suggested that all patients may have some evidence of MRD when such sophisticated techniques are employed.

Explanation of the CDAR (2CDA with Rituximab) Trial

Robert J. Kreitman, M.D.
National Cancer Institute
National Institutes of Health (NIH)

At the NIH, we have begun treating hairy cell leukemia patients, who have had either no or 1 prior courses of cladribine, with a combination of cladribine and rituximab. At this time, the standard practice for this disease is to use cladribine alone for the first treatment, and if needed, to use cladribine alone a 2nd time if and when the disease comes back. This has been the practice since the early 90’s, and the results of treatment with cladribine alone are excellent. For example 85-95% of patients can get into complete remission and about 60% are still in remission 10 years later. When patients do relapse, 75% can get into a 2nd complete remission with the same treatment.

However, nearly 20 years after we began using cladribine, there is no evidence that cladribine cures patients. In fact, with each repeat course of either cladribine or the other purine analog, pentostatin, there is a lower chance for a complete remission, and a higher chance for bone marrow damage and other toxicities. In most patients who have a complete remission after getting cladribine alone, we can detect very low levels of minimal residual disease, and it is believed that over many years these few hairy cells grow back, and if patients live long enough, will cause relapse.

A new strategy is to use rituximab, a biologic drug, to eliminate the minimal residual hairy cells before they grow back, and thereby prevent or at least delay the disease from coming back, along with the need for more chemotherapy. Although rituximab can cause some allergy-type reactions during the first few infusions and temporarily kill normal B-cells, it does not seem to have long-term toxicities like chemotherapy. In study recently reported from MD Anderson, 13 hairy cell patients received cladribine followed 1 month later by 8 weekly infusions of rituximab, and it was tolerated very well with all the patients having complete remissions, and only 1 having minimal residual disease.

At the NIH, we are comparing 2 different times to begin rituximab in patients receiving cladribine for the 1st or 2nd time. All patients receive cladribine by 2-hour infusion daily for 5 days, beginning on day 1. Half of patients receive concurrent rituximab, beginning on day 1 and repeated weekly for a total of 8 doses. Both groups receive rituximab at least 6 months after cladribine, when minimal residual disease is detectable in the blood. We cannot predict which method of beginning rituximab is best. It is possible that delaying it for 6 months is best because that is the time when we expect the clumps of HCL cells to be smallest and easiest to penetrate with rituximab. Although both groups can get rituximab if needed at that time, it might not work as well then if it were already used earlier. On the other hand, getting rituximab at the same time as cladribine may allow the 2 agents to work together.

Regardless, the addition of rituximab to cladribine, either early or late, may be better than waiting for patients to relapse, and in this trial the minimal residual disease is very carefully monitored. This is also true for the trial at MD Anderson, which is still accepting patients. For the NIH trial, all patients begin the first day of treatment at the NIH, and the rest of the treatment may be given either at the NIH or by the patient’s local doctor if desired. Patients are not charged for treatment given at the NIH. The rituximab used for this trial, which is unlikely to be covered by insurance, will be supplied to local doctors if given outside of the NIH.

(C=cladribine 1.5 mg/Kg, 2 hour intravenous infusion daily for 5 days)
(R=rituximab 275 mg/m2, intravenous infusion weekly for 8 doses)

If you or your patient is possibly interested in this trial, please call our clinical staff for more information.

Robert J. Kreitman
Chief, Clinical Immunotherapy Section
Laboratory of Molecular Biology (LMB)
National Cancer Institute (NCI)
National Institutes of Health (NIH)
Building 37 Room 5124b
9000 Rockville Pike
Bethesda, MD 20892
301-496-6947
301-496-1211 (Page)
kreitmar@mail.nih.gov (Email)

Elizabeth Maestri, R.N. or Linda Ellison, R.N.
Clinical Immunotherapy Section
LMB, NCI, NIH
Building 10 Room 10/12N214
9000 Rockville Pike
Bethesda, MD 20892
301-402-5633 or 301-496-9458 (Phone)
240-220-7677 (Fax)
301-496-1211 (Page)
maestrie@mail.nih.gov or
ellisonl@mail.nih.gov

Links to more information:

Information on the NIH trial:

http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=617272&versio...

Information on the MD Anderson trial which is still open:

http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=529071&versio...

European Approach to Induction Therapy and to Combination Therapies in HCL

Francesco Lauria, Francesco Forconi
Ematologia e Trapianti, University of Siena, AOUS, Italy

The article discusses the advantages and disadvantages found in studies when using Cladribine during treatment by intravenous continuous infusion, weekly intravenous infusion, subcutaneous administration, and oral adminisrtation. Furthermore, the article discusses the use of Pentostatin and combination therapy with Rituximab following a purine nucleoside analog.

Please click below to read full article.

The Long-term Outcome for Patients Treated for Hairy Cell Leukaemia

Monica Else, Claire Dearden, Estella Matutes, Daniel Catovsky

Hairy-cell leukaemia (HCL) was first described 50 years ago (Bouroncle et al, 1958) and is recognised as a distinct entity in the WHO classification of haematopoietic tumours (Foucar et al, 2008). Prior to the introduction of the purine analogs pentostatin (Spiers et al, 1984) and cladribine (Piro et al, 1990), median survival was only 4 years (Golomb et al, 1978). However, treatment with these agents has transformed the course of this disease. A number of retrospective studies have reported overall responses in more than 85% of patients with median relapse-free survival up to 15 years (Table 1). The anti-CD20 monoclonal antibody rituximab also has efficacy in HCL, particularly when used in combination with a purine analog (Table 2). This is not surprising, as the density of expression of the CD20 antigen is the highest of all the B-cell malignancies. Kreitman et al (2001 & 2006) have also reported promising results with a recombinant anti-CD22 immunotoxin, with overall responses in 81% and complete responses in 61%.

We recently reviewed again, retrospectively, the data from our RMH/ICR series of 233 patients with HCL, at a median follow-up of 16 years, to investigate the effect of treatment in the very long term (Else et al, 2009). Patients received either pentostatin (n=188) or cladribine (n=45) as first-line therapy.

Please click below to read full article.