Long-term follow-up of 233 patients with hairy cell leukaemia, treated initially with pentostatin or cladribine, at a median of 16 years from diagnosis.

Hairy cell leukaemia (HCL) was first described 50 years ago. Median survival was then 4 years. The purine analogues, introduced in the 1980s, transformed this prognosis. We reviewed data retrospectively from 233 patients, treated with pentostatin (n = 188) or cladribine (n = 45), to investigate the current long-term outlook. Median follow-up was 16 years. There were no significant differences in outcome between the two agents. Overall, the complete response (CR) rate was 80% and median relapse-free survival was 16 years. After relapse (n = 79) or non-response (n = 5), 26 patients received pentostatin and 58 cladribine; 69% achieved CR and median relapse-free survival was 11 years. After third-line therapy (n = 23), 50% achieved CR and median relapse-free survival was 6.5 years. However, CRs were equally durable, whether after first, second or third-line therapy. Complete responders and those with both haemoglobin >100 g/l and platelet count >100 x 10(9)/l before treatment had the longest relapse-free survival (P < 0.0001). Patients still in CR at 5 years had only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease improved with the monoclonal antibody rituximab, combined with either purine analogue. Overall only eight patients died of HCL-related causes. Patients achieving a CR can expect a normal lifespan.

Combinations of ZAP-70, CD38 and IGHV mutational status as predictors of time to first treatment in CLL.

ZAP-70, CD38 and IGHV mutations have all been reported to have prognostic impact in chronic lymphocytic leukemia (CLL), both individually and in paired combinations. We aimed to determine whether the combination of all three factors provided more refined prognostic information concerning the treatment-free interval (TFI) from diagnosis. ZAP-70, CD38 and IGHV mutations were evaluated in 142 patients. Combining all three factors, the ZAP-70-/CD38-/Mutated group showed the longest median TFI (62 months, n = 37), ZAP-70+/CD38+/Unmutated cases the shortest (11 months, n = 37) and cases discordant for > or = 1 factor, an intermediate TFI (27 months, n = 68) (p = 0.006). Analysis of discordant cases revealed values that were otherwise masked when measuring single prognostic factors. The presence or absence of cytogenetic abnormalities did not explain the variability among discordant cases. Simultaneous analysis of ZAP-70, CD38 and IGHV mutations in CLL provides more discriminatory prediction of TFI than any factor alone.

The role of rituximab in combination with pentostatin or cladribine for the treatment of recurrent/refractory hairy cell leukemia.

BACKGROUND: The purine analogs pentostatin and cladribine have revolutionized the treatment of hairy cell leukemia (HCL) with overall responses in greater than 85% of patients and a median progression-free survival of up to 15 years. They continue to be effective at second- and even third-line therapy; however, alternative treatments are needed for patients who are or have become refractory to these agents or whose remissions are shorter with each course of therapy. METHODS: The authors conducted a retrospective review of 8 patients who received pentostatin or cladribine combined concurrently (n = 6 patients) or sequentially (n = 2 patients) with rituximab at second-line therapy (n = 3 patients) and at subsequent lines of therapy (n = 5 patients). Results from a previously reported database of 219 patients with HCL (73 patients who received second-line therapy and 20 patients who received third-line therapy) were used as a historic control group against which to measure benefit. RESULTS: All 8 patients responded to therapy, with 7 complete responses (CRs) (87.5%) and minimal toxicity. All patients who had CRs were negative for minimal residual disease (MRD). At a median follow-up of 29 months (range, 5-39 months) 1 patient developed recurrent disease, and the estimated 2-year recurrence rate was 20% (0% after second-line therapy and 25% after subsequent lines of therapy). In the historic control group, the CR rates were 70% after second-line therapy and 45% after third-line therapy, and the recurrence rates at 2 years were 15% and 33%, respectively. CONCLUSIONS: The combination of purine analogs with rituximab was safe and effective for patients with recurrent and/or refractory HCL, and the current results suggested an added benefit compared with standard treatment.

T-cell large granular lymphocyte leukemia: A report on the treatment of 29 patients and a review of the literature.

BACKGROUND: To the authors' knowledge, there is no standard treatment for patients with T-cell large granular lymphocyte (LGL) leukemia. Available data are limited by patient numbers and coexisting pathologies. METHODS: The authors report on the use of immunosuppressants (cyclosporin A [CSA] and low-dose oral methotrexate [MTX] given continuously) and cytotoxic agents in the treatment of 29 patients with T-cell LGL leukemia age over the past 20 years. RESULTS: The overall response rate (ORR) to MTX (n = 8 patients) was 85.7% (complete hematologic response [CHR] rate, 14.3%; partial response [PR] rate, 71.4%) with dose-dependent responses observed and safe usage of doses >10 mg/m2 per week in 2 patients. The ORR to CSA (n = 23 patients) was 78.2% (CHR rate, 30.4%; PR rate, 47.8%). The median time to response for both agents was 1 month. Toxicity, although it was minor in most patients and was more common in the CSA group, included second malignancies in 5 patients. An ORR of 67% (all CHR) was attained with pentostatin (n = 4 patients); recurrences developed after a median of 4.6 years. Successful retreatment with pentostatin was possible but with increasing drug resistance. Cyclophosphamide induced CHR that lasted >7 years with bone marrow clearance in 1 of 4 patients. Alemtuzumab induced a PR in 1 patient who had refractory disease. CONCLUSIONS: Both MTX and CSA were efficacious in the treatment of T-cell LGL leukemia but generally required long-term maintenance therapy. The authors highlight the risks of second malignancies and persistence of bone marrow disease. Although MTX and CSA were effective as first-line therapy, alemtuzumab and pentostatin merit further investigation, particularly for refractory disease.

Zeta-chain associated protein 70 and CD38 combined predict the time to first treatment in patients with chronic lymphocytic leukemia.

BACKGROUND: Zeta-chain associated protein (ZAP)-70 has been proposed as a surrogate marker for immunoglobulin heavy-chain variable region (IgVH) mutation in chronic lymphocytic leukemia (CLL), but it is still not clear whether it is an independent prognostic factor. METHODS: The authors evaluated ZAP-70 expression by flow cytometry in 201 untreated patients and correlated ZAP-70 levels with CD38 expression, genetic abnormalities detected by fluorescence in situ hybridization (FISH), and the time from diagnosis to first treatment. RESULTS: Fifty-seven patients (28%) were positive for ZAP-70 (> or = 20%). Positive ZAP-70 status was associated with advanced disease stage, atypical morphology, CD38-positive status, trisomy 12, del(6q), or no detectable abnormalities; negative ZAP-70 status was correlated with del(13q) as a sole abnormality. The treatment-free interval (TFI) was 17.7 months for ZAP-70-positive patients and 44.6 months for ZAP-70-negative patients (P < 0.001). Multivariate analysis in 117 patients identified advanced stage, CD38 > or = 7%, and the absence of del(13q) as a sole abnormality as independent factors for short TFI. Excluding FISH, ZAP-70 status acquired independent prognostic value along with CD38 status. The authors proposed a risk model that combines ZAP-70 and CD38 to identify patients who are likely to progress. When both markers were positive, the TFI was 12 months; when both were negative, the median TFI was 54 months; a median TFI of 26 months was observed in patients who had discordant results (P < 0.00001). CONCLUSIONS: The current findings suggested that both ZAP-70 and CD38 should be tested prospectively in all patients with early-stage CLL.

The efficacy of alemtuzumab for refractory chronic lymphocytic leukemia in relation to cytogenetic abnormalities of p53.

We reviewed the efficacy of alemtuzumab in the treatment of 28 patients with refractory chronic lymphocytic leukemia (CLL) in whom p53 status was known. Overall responses of 53.6% (complete responses 17.9%) were attained with no significant difference between patients with (50%) or without (55%) p53 deletion (p=0.214). We confirm the efficacy of alemtuzumab in refractory CLL irrespective of p53 deletions, and advocate its introduction earlier in disease course.

Long remissions in hairy cell leukemia with purine analogs: a report of 219 patients with a median follow-up of 12.5 years.

BACKGROUND: Both pentostatin and cladribine have efficacy in hairy cell leukemia (HCL), but it is not known which agent achieves better results. METHODS: We reviewed a series of 219 patients with HCL, with median follow-up from diagnosis of 12.5 years (range 1.0 -34.6 yrs), treated with either pentostatin (n = 185) or cladribine (n = 34), to compare these agents and assess the potential for cure. RESULTS: Overall response to pentostatin was 96% with a complete response (CR) in 81% and a median disease-free survival (DFS) of 15 years. Response to first-line cladribine was 100% with a CR in 82% and DFS of 11+ years. The relapse rates at 5 years and 10 years were 24% and 42%, respectively, with pentostatin, and 33% and 48% with cladribine. Survival at 10 years was respectively 96% and 100%. CR rates decreased with each sequential relapse through 69% to 45% (P < or = 0.001). Patients achieving CR after first-line treatment had a significantly longer DFS (P = 0.00007) than those achieving a partial response; a similar result was seen after second-line therapy (P = 0.00001). DFS also declined with sequential treatment (P = 0.00005). CONCLUSION: We have shown equivalent efficacies for both agents in the treatment of HCL, with DFS showing no plateau. True cure in HCL remains elusive, but the addition of monoclonal antibodies may be beneficial. Our results suggest that achieving CR should remain the main goal of treatment.

Histopathology of the spleen in T-cell large granular lymphocyte leukemia and T-cell prolymphocytic leukemia: a comparative review.

We review retrospectively the spleen histology in 8 patients with T-cell large granular lymphocyte (LGL) leukemia and 4 with T-cell prolymphocytic leukemia (T-PLL) to identify characteristic patterns of involvement and to distinguish such patterns from those described in other low grade B- and T-cell malignancies. Moderate splenic enlargement with red pulp expansion due to lymphocytic infiltration was characteristic of LGL leukemia. Abnormal lymphocytes expressed cytotoxic granule proteins and were consistently CD45RO and CD5 negative in contrast to normal red pulp T cells. This infiltration respected anatomic boundaries with encroachment but no invasion of white pulp areas. Unlike in hairy cell leukemia, the main differential diagnosis for red pulp lymphocytosis, the white pulp was not only preserved in T-cell LGL leukemia but showed germinal center hyperplasia with expansion of the mantle zones. By comparison, T-PLL spleens showed marked red pulp lymphoid infiltration by medium-sized cells with irregular nuclei and prominent eosinophilic nucleoli. T-PLL lymphocytes, unlike LGLs, were more invasive, infiltrating the spleen capsule as well as white pulp areas. T-cell prolymphocytes did not express cytotoxic granule proteins or NK-cell markers, were CD5+, CD45RO+ like normal spleen T cells, were CD2+, CD3+, CD45+, CD43+, TCRbeta+, but CD25-, CD30-, ALK-1-, TRAP-, DBA44-, and TdT-. Expression of CD4 and CD8 in these cells mirrored that of circulating T-PLL cells. These observations on the morphologic and immunohistochemical appearances of the spleen in T-cell LGL leukemia and T-PLL may aid diagnosis of these uncommon T-cell disorders, particularly T-cell LGL leukemia, where presentation may be cryptic and where unique pathognomonic features, are absent.

Delayed response to fludarabine in lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia.

We retrospectively reviewed time to response and incidence of delayed responses in 13 patients with lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia (LPL/WM) treated with fludarabine with or without cyclophosphamide. During follow-up post-treatment, seven delayed responses (54%) were observed, improving the initial overall response rate of 61% to a final response rate of 77%.

Pregnancy improves neutropenia in T-cell large granular lymphocyte leukaemia.

The effect of pregnancy on T-cell large granular lymphocyte (LGL) leukaemia has not been previously described. We retrospectively reviewed the clinical features of three patients with T-cell LGL leukaemia; each of them had one or more pregnancies during disease evolution. Pregnancy was associated with sustained improvement in neutrophil count and concurrent reduction in lymphocytosis. Neutropenia returned in the non-pregnant state in all cases. A similar effect, induced by exogenous progesterone in one patient, suggests a role for progesterone in overcoming mechanisms of neutropenia in this disease. Pregnancy thus appears to have a beneficial effect on neutrophil count in T-cell LGL leukaemia.

Lessons from a case of T-cell large granular lymphocytic leukaemia suggesting that immunomodulatory therapy is more effective than intensive treatment.

Leukemia treatment strives to eradicate the malignant clone. With T-cell large granular lymphocytic (LGL) leukemia, the onus of treatment appears to be modification of the disease rather than eradication of the clone. We describe a case of T-cell LGL leukemia where aggressive, eradicative type therapy proved ineffective. The patient achieved hematological response to low dose oral methotrexate after failing to respond to and/or tolerate eight previous treatments including CAMPATH-1H and peripheral blood stem cell transplantation. We highlight the resistant nature of the LGL clone and discuss the relative merits of immunomodulatory type therapy in this disease.

Granulomatous slack skin disease--disease features and response to pentostatin.

Granulomatous slack skin disease (GSSD) is a rare condition characterized clinically by redundant skin folds, which show a predilection towards flexural areas, and histologically by a granulomatous T-cell infiltrate and loss of elastic fibres. The disease is often indolent, although rapid progression and transformation have been described. There is much debate as to whether this condition is a subset of mycosis fungoides or a separate disease entity in itself. We describe a case of GSSD with unique manifestations including granulomatous bone marrow involvement and hypercalcaemia. The patient has twice achieved a good response to pentostatin after failure of combination chemotherapy. This is the first report of the successful use of the purine analogue pentostatin in the management of GSSD.

Growth factors in haematological cancers.

Since their discovery just under a century ago, growth factors (GFs) have been used almost ubiquitously in haematology. Many haematological cancers are associated with bone marrow failure, either as a direct consequence of the disease or its treatment. Colony stimulating factors (CSFs) have been used to address the problems associated with the resulting cytopenias, however, concerns about the potential leukaemogenic effects of some of these CSFs led to a degree of initial hesitancy in usage, particularly in the management of acute myeloid leukaemia (AML). This has now been largely overcome. Other limitations have included cost and side effect profiles (the latter particularly with the multilineage factors). There has been wide variation locally, nationally and internationally in the usage of GFs. The American Society of Clinical Oncologists (ASCO) attempted to rationalise the usage of GFs by producing a consensus document enumerating the evidence-based indications for use of GFs. There is little information on cost effectiveness, this remains an important issue for the future. Peripheral blood stem cell transplantation (PBSCT) has revolutionised the management of many malignant conditions and has contributed to the increased use of growth factors. Many other indications are emerging for GFs used singly or in combination. Current clinical applications of GFs include: i) amelioration of cytopenias following chemotherapy and stem cell transplantation, ii) chemotherapy dose maintenance and escalation, iii) chemosensitisation and modification of disease states, iv) optimisation of methods for mobilisation of progenitor stem cells, v) immunotherapy, and vi) as therapeutic targets for treatment of haematolgical malignancies.