Rationale for the evaluation of renal functional reserve in allogeneic stem cell transplantation candidates: a pilot study.

Background: The main purpose of our study was to evaluate the ability of renal functional reserve (RFR) to stratify the risk of acute kidney injury (AKI) occurrence within 100 days of hematopoietic stem cell transplantation (HSCT) and to predict any functional recovery or the onset of chronic kidney disease. A secondary aim was to identify the clinical/laboratory risk factors for the occurrence of AKI. Methods: The study design is prospective observational. We enrolled 48 patients with normal basal glomerular filtration rate (bGFR) who underwent allogenic HSCT. A multiparameter assessment and the Renal Functional Reserve Test (RFR-T) using an oral protein load stress test were performed 15 days before the HSCT. Results: Different RFRs corresponded to the same bGFR values. Of 48 patients, 29 (60%) developed AKI. Comparing the AKI group with the group that did not develop AKI, no statistically significant difference emerged in any characteristic related to demographic, clinical or multiparameter assessment variables except for the estimated GFR (eGFR). eGFR ≤100 mL/min/1.73 m2 was significantly related to the risk of developing AKI (Fisher's exact test, P = .001). Moreover, RFR-T was lower in AKI+ patients vs AKI- patients, but did not allow statistical significance (28% vs 40%). In AKI patients, RFR >20% was associated with complete functional recovery (one-sided Fisher's exact test, P = .041). The risk of failure to recover increases significantly when RFR ≤20% (odds ratio = 5.50, 95% confidence interval = 1.06-28.4). Conclusion: RFR identifies subclinical functional deterioration conditions essential for post-AKI recovery. In our cohort of patients with no kidney disease (NKD), the degree of pre-HSCT eGFR is associated with AKI risk, and a reduction in pre-HSCT RFR above a threshold of 20% is related to complete renal functional recovery post-AKI. Identifying eGFR first and RFR second could help select patients who might benefit from changes in transplant management or early nephrological assessment.

[The genetic basis of post-bone marrow transplant thrombotic microangiopathy: is this the last piece of the puzzle?]

Transplant-associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic stem cell transplantation (HSCT) associated with kidney injury and significant mortality. Recent studies indicate that dysregulation of the alternate complement pathway may be at the basis of the development of TA-TMA. Currently, there are no pre-transplant screening tools to identify patients at risk. To explore the mechanism of TA-TMA, we performed a genetic study that allowed us to identify the deletion of the CFHR3-CFHR1 region in homozygosity. We report the clinical case of a 47-year-old woman who underwent haploidentical HSCT complicated by TA-TMA confirmed by renal biopsy. The patient discontinued treatment with calcineurin inhibitors (potential inducers of TA-TMA) with a brief introduction of prednisone until complete resolution of renal damage and microangiopathy. Identifying genetic variants that affect the mechanism of the alternate complement pathway could help in the stratification of the risk of TA-TMA and in implementing a personalized therapeutic approach.

Low-dose oral fludarabine plus cyclophosphamide in elderly patients with untreated and relapsed or refractory chronic lymphocytic Leukaemia.

Fludarabine plus cyclophosphamide (FC) at conventional doses is an effective treatment for chronic lymphocytic leukaemia (CLL). However, FC at standard doses may give hematological and non-hematological toxicity, predominantly in the elderly. Intravenous or oral low-dose FC regimens remain highly effective in elderly patients with Low-Grade Lymphomas other than CLL and are well tolerated. We tested efficacy and toxicity of oral FC at reduced doses in 26 elderly patients (median 71 years) with previously untreated (UT-CLL, n = 14) or relapsed/refractory CLL (R-CLL, n = 12), unfit for conventional treatments. Twentyfour-of-26 (92%) patients (14/14, 100% UT-CLL; 10/12, 83.5% R-CLL) obtained a response, with 12/26 (46%) complete responses (9/14, 64.2% in UT-CLL; 3/12, 25% in R-CLL). Non-hematological toxicity was mild and myelosuppression was documented in 8/26 (31%) patients (4/14, 28% UT-CLL; 4/12, 33% R-CLL). With a median follow-up of 24 months, median event-free survival was 48 months with no differences between UT-CLL and R-CLL and all responders were alive. Low-dose oral FC treatment showed good efficacy in both untreated and refractory/relapsed CLL. The treatment is useful in elderly patients who cannot benefit of more aggressive schedules and is easy to administer on an outpatient basis.

Low-dose oral fludarabine plus cyclophosphamide as first-line treatment in elderly patients with indolent non-Hodgkin lymphoma.

Twenty-five elderly patients with untreated indolent non-Hodgkin lymphoma were treated with oral fludarabine 25 mg/m(2)/d (40 mg total dose) and cyclophosphamide 150 mg/m(2)/d, both for four consecutive days, repeated every 28 d for four cycles. In all, 21 (84%) patients were responsive: 10 patients achieved complete remission while partial response was obtained in 11. During an observation period of 37 months, there was an overall survival rate of 70% and a median event-free survival of 20 months. Haematological and extra-haematological toxicity were mild. This reduced-dose Flu-based oral regimen showed good efficacy and was simple to administer on an outpatient basis.

The role of MDR-related proteins in the prognosis of adult acute myeloid leukaemia (AML) with normal karyotype.

Cytogenetic abnormalities are among the most important factors affecting the outcome of patients with acute myeloid leukaemia (AML), but approximately 40-50% of AML cases display a normal karyotype at diagnosis. Multidrug resistance (MDR) proteins overexpression is associated with worse prognosis in acute leukaemias, but its role in normal karyotype AML is less defined. We analysed the expression of P-glycoprotein (PGP), MDR-related protein (MRP) and lung resistance protein (LRP) in 135 adult patients with normal karyotype AML and its correlation with other biological features of the disease, to evaluate the impact of MDR proteins on response to therapy and on survival. Increased PGP expression was associated with lower rate of complete remission (CR; p = 0.006), similarly to advanced age. Cases overexpressing PGP displayed also a shorter event-free survival (EFS; 4 vs. 10 months, p = 0.035) and the increased expression of at least one MDR protein was associated with a reduced overall survival (OS; p = 0.038). Also age was predictive of worse prognosis. Our data confirm the prognostic role of MDR proteins, in particular of PGP, also in AML patients with normal karyotype at diagnosis. This finding could be used to stratify patients with different prognosis and to design risk-adapted therapeutic strategies.

Role of interferon-alpha administration after 2-deoxycoformycin in the treatment of hairy cell leukemia patients.

BACKGROUND AND OBJECTIVE: Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder which is treated effectively by interferon-alpha (IFN-alpha), deoxycoformycin (DCF) and 2-clorodeoxyadenosine (2-CdA). As a third of patients treated with DCF do not achieve a complete remission (CR) and many of them tend to relapse, we evaluated the potential role of IFN-alpha, randomly administered after DCF, in increasing the number of patients attaining CR and/or duration of CR. METHODS: From March 1997 to December 2000, 167 previously untreated HCL patients, from 37 Italian institutions, were enrolled in the study. A total of 138 males and 29 females, with a median age of 55 yr were included in the study. All patients received six courses of DCF 4 mg/m(2) i.v. every other week and then two additional courses once a month. Complete and partial responders were randomly assigned to receive or not receive IFN-alpha at a dose of 3 MU s.c. three times a week for 6 months. RESULTS: Of the 167 patients enrolled in the study, 145 (86.8%) obtained a CR or a partial remission (PR) and were therefore suitable for randomization. One hundred and thirty-five patients were successively randomized to receive IFN-alpha (63 cases; arm A) or not (72 cases; arm B). Progression of disease was observed in eight (arm A) and 12 (arm B) patients with a median time of 27.8 and 26.9 months, respectively. As far as the improvement in response was concerned, no significant difference in the two subgroups was observed. In fact, five patients in arm A and six patients in arm B showing a good PR at the end of DCF therapy, subsequently attained a late CR. CONCLUSIONS: From our data there does not appear to be any significant role for IFN-alpha in improving the proportion and the duration of CR in HCL patients previously treated with DCF.

Activity of rituximab monotherapy in refractory splenic marginal zone lymphoma complicated with autoimmune hemolytic anemia.

We describe the case of a 61-year-old patient with refractory splenic marginal zone lymphoma and secondary autoimmune hemolytic anemia, both successfully treated with rituximab. This case demonstrates that rituximab monotherapy might also be a valid therapeutic approach in marginal zone lymphoma and autoimmune hemolytic anemia after failure of first-line treatment. Maintenance therapy, although expensive, could be useful to improve event-free survival in patients with unfavorable clinical behavior.

Absence of surface CD27 distinguishes hairy cell leukemia from other leukemic B-cell malignancies.

Surface expression of CD27 was evaluated in 75 mature leukemic B-cell neoplasms. All cases other than hairy cell leukemia (HCL) expressed CD27. Intensity was significantly higher in chronic lymphocytic leukemia. Lack of CD27 in 17/17 HCL contrasted with expression of this marker in 5/5 splenic lymphomas with villous lymphocytes. Lack of CD27 is a new distinctive feature of HCL among B-cell malignancies.

Low-dose oral fludarabine plus cyclophosphamide in elderly patients with chronic lymphoproliferative disorders.

A synergistic effect of fludarabine (FLU) and cyclophosphamide (CY) has been extensively demonstrated in the treatment of chronic lymphoproliferative disorders (CLD), although a high incidence of severe neutropenia and infectious complications, particularly in elderly patients, have been reported. Based on a previous clinical experience in elderly CLD patients treated with a combination of low-dose intravenous (i.v.) FLU and CY in whom we obtained good response rates and negligible toxicity, we tested efficacy and safety of the new oral formulation of FLU combined with CY at low doses. A total of 28 elderly patients with relapsed/refractory or untreated CLD were treated with oral FLU and CY (25 and 150 mg/m2 respectively, both for 4 days every 4 weeks). The treatment design consisted in four consecutive courses and the median value of courses per patient was 3. Overall, 25 out of 28 evaluable patients were responsive to the treatment (six CR and 19 PR; ORR 89%), while the remaining three patients did not show any appreciable response (two progressive and one stable disease). Hematological toxicity was low in the majority of patients (grade 2-3 neutropenia/anemia in 8/28 cases); however, two fatal infections occurred and one additional patient died because of disease progression. Extra-hematological toxicity was generally mild. This preliminary report suggests that oral combination of FLU and CY at low dose is effective as the i.v. formulation and standard doses, since it may induce rapid responses in about 90% of elderly patients with CLD, with an acceptable toxicity.

Trisomy 12 and t(14;22)(q32;q11) in a patient with B-cell chronic lymphocytic leukemia.

Recurrent cytogenetic abnormalities are typically found in about one third of B-cell chronic lymphocytic leukemia patients (B-CLL) by standard cytogenetic analysis and their prognostic relevance is well known. We report a case of a B-CLL patient showing both trisomy 12 and a t(14;22)(q32;q11). Trisomy 12 is often associated with aggressive disease and resistance to chemotherapy, however, our patient is in good health and currently untreated after 7 years, suggesting in this case a relatively good prognosis and a questionable role for translocations involving the 14q32 locus.

Efficacy of rituximab in the treatment of refractory chronic lymphocytic leukemia patient with bone marrow aplasia.

Recently, several reports have been published claiming the efficacy of anti-CD20 monoclonal antibody (rituximab) in the treatment of B-cell chronic lymphocytic leukemia (B-CLL) and some related autoimmune complications. We used anti-CD20 monoclonal antibody in a patient with advanced stage and heavily pre-treated B-CLL with a concomitant bone marrow aplasia requiring a remarkable transfusional support of both red blood cells and platelets. The treatment was conducted according to standard dosage and schedule and the patient did not experience any severe side effect. A progressive reduction of transfusions and a certain recovery of bone marrow cellularity was observed after six months from the end of therapy. This case suggests that rituximab can play a role in this subset of B-CLL patients with very few effective therapeutic options and in which the clinical features may be due both to neoplastic proliferation and concomitant autoimmune disorder.