Guido Pagnucco

Adverse events occurring during bone marrow or peripheral blood progenitor cell infusion: analysis of 126 cases

Bone marrow (BM) and/or peripheral blood progenitor cells (PBPC) given after high-dose chemo-radiotherapy are commonly cryopreserved. Re-infusion of the thawed product can cause cardiovascular and other complications. We compared two groups of adult patients receiving autologous BM or PBPC transplant to assess the incidence of adverse events occurring during infusion. Fifty-one patients received BM, and 75 PBPC. The two groups were comparable in respect of age, total volume infused, quantity of dimethylsulfoxide (DMSO) and number of polymorphonuclear neutrophils. Patients receiving PBPC had a higher number of nucleated cells per kg of body weight; those in the BM group received a significantly greater quantity of red cells. Non-cardiovascular complications occurred in 19% and 8% of patients rescued by BM and PBPC respectively. The incidence of hypertension was 21% in the BM and 36% in the PBPC group. Asymptomatic hypotension was more frequent in PBPC patients (P < 0.001). bradyarrhythmia was noticed in two of 75 pbpc patients and in 14 of 51 bm patients (P < 0.001). in the former group one patient had heart block; he died of renal failure 10 days later. bradycardia and hemoglobinuria were more common in patients receiving bm where a higher concentration of red cells was present (P < 0.001). since bradyarrhythmias may be a life-threatening complication we advise continuous careful monitoring during infusion of thawed bm. the strong correlation between bradycardia and red blood cell contamination suggests the use of purified products with a very low red cell content.

Myelofibrosis in chronic granulocytic leukaemia: clinicopathologic correlations and prognostic significance

Summary. We performed 221 marrow trephine biopsies in 139 patients with Ph1‐positive (Ph1‐+) chronic granulocytic leukaemia (CGL) in order to assess the incidence, degree and prognostic significance of marrow fibrosis (MF) at various stages of the disease. We also attempted to elucidate the relationship between development of MF and the various clinical and haematological features of CGL. A significant correlation was found between the amount of fibrosis (graded from 0 to 3) and the stage of CGL, indicating that major fibrotic changes are associated with accelerated or blastic disease. Survival studies performed to assess the prognostic significance of the various degrees of MF, showed a progressively worse life‐expectancy from grade 0 to grade 3 fibrosis. Multivariate regression analysis indicated Hb level, age, number of marrow megakaryocytes (MKs), time from diagnosis as the features most significantly correlated with the degree of MF. This study demonstrates that the natural history of CGL involves a progressive increase in reticulin deposition towards severe MF, although the rate of this progression varies widely. Monitoring changes of fibrosis with sequential biopsies could give a measure of the rate of progression of the disease and help in prognostic assessment of CGL patients. Our findings also confirm that among marrow features the number of MKs is the cytological variable most significantly correlated with MF.

Hairy Cell Leukemia: a Clinical Review Based on 725 Cases of the Italian Cooperative Group (ICGHCL)

The Italian Registry for hairy cell leukemia (HCL) has recorded 725 patients with HCL diagnosed over 25 years. We analysed this large series of patients with the aim of providing an evaluation of changes in clinical presentation, impact of initial therapy and modifications in prognostic factors over the period of two decades.

Fludarabine, cyclophosphamide, and dexamethasone (FluCyD) combination is effective in pretreated low-grade non-Hodgkin's lymphoma

PURPOSE Fludarabine phosphate is effective as a single agent in low-grade non-Hodgkins lymphoma (NHL). Combined with other antineoplastic agents it enhances the antitumor effect. Our aim was to define the therapeutic efficacy and toxicity of a combination of fludarabine, cyclophosphamide and dexamethasone (FluCyD) in patients with advanced low-grade lymphoma. PATIENTS AND METHODS Twenty-five adults with pretreated advanced-stage low-grade NHL were treated with three-day courses of fludarabine 25 mg/m2/day, cyclophosphamide 350 mg/m2/day, and dexamethasone 20 mg/day, every four weeks for a maximum of six courses. RESULTS Of the 25 patients, 18 (72%) responded, 8 (32%) achieving CR and 10 (40%) PR. Seven were failures. The median follow-up was 21 months (5-26). Eight CR patients remain in CR after 5-21 months. Of 10 PR patients, 3 are in continuous PR without further treatment after 12, 17 and 18 months. Myelosuppression was the most prevalent toxic effect. Although severe granulocytopenia (granulocyte count nadir < 500/microliter) and thrombocytopenia (platelet count nadir < 50,000/microliter) occurred in only 10% and 16% of courses, respectively, slow granulocyte or platelet count recovery caused delay of 40% of the courses. Nine patients (36%) required discontinuation of therapy because of persistent granulocytopenia and/or thrombocytopenia: three after one course, three after 2-4 courses, and three after five courses. Thirteen infectious episodes in 11 patients complicated 11% of courses. Two of 10 patients monitored for the circulating EBV load showed increased viral load. One of these developed aggressive lymphoma. CD4+ lymphocytes declined from a pre-therapy median value of 425/microliter to 141/microliter post-treatment (P = 0.001). Non-hematologic toxicities were rare and mild. CONCLUSIONS The combination of fludarabine with cyclophosphamide and dexamethasone is effective in pretreated advanced-stage low-grade NHL. It may broaden the range of therapeutic options in the salvage treatment of these patients. The main toxicity of this combination is prolonged myelosuppression that may cause treatment delay or withdrawal. The benefit of adding granulocyte colony-stimulating factor, particularly in patients with poor marrow reserve, needs to be investigated.

A sequence of immuno‐chemotherapy with Rituximab, mobilization of in vivo purged stem cells, high‐dose chemotherapy and autotransplant is an effective and non‐toxic treatment for advanced follicular and mantle cell lymphoma

Summary. Options for relapsed/refractory indolent lymphoma include chemotherapy, immunotherapy and high‐dose therapy with autologous support. The best combination of these approaches, however, is not defined. We treated 10 patients with relapsed/refractory follicular (n = 7) or mantle cell lymphoma (n = 3) using chemotherapy, immunotherapy, high‐dose therapy and autotransplant in a sequence of four phases, each designed to play a specific role in tumour eradication. After the debulking with VACOP‐B (doxorubicin, cyclophosphamide, etoposide, vincristine, prednisone, bleomycin) (phase 1), 9/10 patients responded but none achieved a molecular response. After the immuno‐chemotherapy phase, which combined Rituximab with vincristine and cyclophosphamide, seven patients were in complete response (CR) and three in good partial response (PR), and all those with a molecular marker of disease showed a disappearance of the signal from marrow and blood. Phase 3, which coupled high‐dose cytarabine with Rituximab, was effective in mobilizing an adequate number of progenitor cells that were polymerase chain reaction negative in all informative cases. Phase 4 consisted of high‐dose therapy with autologous support followed by two doses of Rituximab. Autograft was performed in nine patients. The haematopoietic recovery was as expected. This sequence of chemotherapy, immuno‐chemotherapy, stem cell mobilization with in vivo purging and autotransplant, organized in four blocks of treatment, was simple to administer and devoid of toxic effects. It permits rapid attainment of clinical and molecular response and enables the harvest of lymphoma‐free peripheral blood progenitor cells even in heavily pretreated patients with relapsed or refractory disease.

The immunosuppression and potential for EBV reactivation of fludarabine combined with cyclophosphamide and dexamethasone in patients with lymphoproliferative disorders

Fludarabine is effective in chronic lymphocytic leukaemia (CLL) and low‐grade non‐Hodgkins lymphoma (NHL). A major side‐effect of this purine analogue is immunosuppression which may favour opportunistic infections. Additionally, impairment of immunosurveillance might promote Epstein‐Barr virus (EBV) reactivation and possibly favour transformation to high‐grade malignancy. The aim of this study was to evaluate the immunosuppression‐related effects of the fludarabine‐based combination Flucyd in advanced low‐grade NHL or CLL by serially monitoring T‐lymphocyte subsets, opportunistic infections, EBV‐reactivation, and histologic transformation. 24 patients with advanced NHL (n = 21) or CLL (n = 3) received fludarabine 25 mg/m2/d + cyclophosphamide 350 mg/m2/d + dexamethasone 20 mg/d in 3 d courses for a maximum of six courses. The overall response rate was 79% (eight CR, 11 PR, five failures); 11 patients relapsed or progressed between 3 and 19 months from response, and eight are in CR or PR at 3–27 months. The CD4+ lymphocyte counts decreased significantly during therapy from a median of 484/μl pre‐treatment (range 142–1865) to a median of 198/μl (71–367). In 19 responders monitored off therapy every 3 months until relapse/progression, CD4+ counts were persistently low with minimal recovery over time. During treatment, 16 infections occurred in 11/24 patients. No delayed opportunistic infections occurred in responders while off therapy. The circulating EBV DNA load serially measured in 19 patients by a quantitative PCR assay showed an increase in four patients during treatment. A lymph node biopsy performed in two of these was PCR positive for EBV DNA, whereas LMP1 and EBERs were negative. Six NHL patients evolved into high‐grade B‐cell NHL. In conclusion, fludarabine combined with cyclophosphamide and dexamethasone is an effective therapy for recurrent indolent lymphoma. This combination produces prolonged T‐lymphocytopenia and has the potential to reactivate a latent EBV infection. T‐cell dysfunction, however, is not associated with higher incidence of clinical opportunistic infections and does not adversely influence clinical outcome.

Plasma cell leukemia: A report on 15 patients

Plasma cell leukemia (PCL) can be considered the leukemic variant of multiple myeloma. The diagnosis is based on hematological features, including a plasmacytosis exceeding 2 × 109/l and any evidence of a clonal plasma cell proliferation. There are two forms of PCL: the primary form occurring in individuals without preceding multiple myeloma, and the secondary form arising as a late manifestation in patients with multiple myeloma. From 1974 to 1988 we diagnosed 8 primary PCL cases out of a total 301 multiple myeloma cases (incidence, 2.6%) and a total of 847 acute leukemia cases (incidence, 0.9%). During the same period we observed in 7 multiple myeloma patients a terminal PCL, for an incidence of PCL in myeloma of 2.3%. Most clinical characteristics were similar in both types of plasma cell leukemia. In particular we found no difference in the average age and in the incidence of bone pain, hepatosple‐nomegaly, lytic bone lesions. None of our cases showed a clinically relevant lymphade‐nopathy either as presenting symptom or during the course of the disease. The values for hemoglobin, leukocytes, plasma cells, serum creatinine and calcium did not differ significantly between the two groups of patients. The median survival was 7 months for patients with primary PCL and 1 month for patients with secondary PCL. 5 of the 8 patients with primary PCL obtained a response to conventional myeloma therapy including single alkylating agents, with a duration ranging from 7 to 44 months. Only 1 of the patients with secondary PCL had a partial response after combination chemotherapy.

Randomized clinical study comparing aggressive chemotherapy with or without G-CSF support for high-risk myelodysplastic syndromes or secondary acute myeloid leukaemia evolving from MDS

One hundred and five consecutive primary high‐risk myelodysplastic syndromes (MDS) or secondary acute myeloid leukaemia (sAML) evolving from MDS (performance status 0–3, ECOG) entered this study. Induction chemotherapy (CT) consisted of idarubicine 12 mg/m2 i.v. on days 1 and 2, etoposide 60 mg/m2/12 h i.v. for 5 d, Ara‐C 120 mg/m2/12 h i.v. for 5 d (one or two courses). Patients were randomized to receive or not G‐CSF (5 μg/kg/d subcutaneously 48 h after the end of CT). 52 cases underwent CT alone and 53 CT+G‐CSF. The CT + G‐CSF patients had a significantly shorter duration of neutropenia (8 v 16 d) with a lower incidence of infections and significantly better responses (CR+PR: 74% v 52%, P < 0.05). 40 patients entered CR: 17 with CT and 23 with CT+G‐CSF. Responders underwent two consolidation courses with the same CT, followed by high‐dose Ara‐C (2 g/m2 every 12 h for 3 d). Most CRs were clonal. At present 21 responders have relapsed (median relapse‐free survival 4.5 months). Eight responders received an allo‐BMT, six are alive in CR 7–57 months post‐transplant. Therefore allo‐BMT only increases the chance of a long survival and possible cure. In conclusion, CT+G‐CSF did not prolong either CR duration or survival; the growth factor support, however, increased the number of allo‐transplantable cases by inducing higher remission rates and improving clinical conditions.

The role of systemic high-dose cytarabine in the treatment of central nervous system leukemia clinical results in 46 patients

Background. Given the good penetration of systemic high‐dose cytarabine (HDara‐C) into the cerebrospinal fluid (CSF), this approach was used to treat patients with central nervous system (CNS) leukemia, either isolated or with concurrent extraneurologic disease (END).

Systemic high-dose ara-C for the treatment of meningeal leukemia in adult acute lymphoblastic leukemia and non-Hodgkin's lymphoma.

Considering the good penetration of systemic high-dose ara-C (HDara-C) into the CNS, we used this approach for treating overt meningeal leukemia, either isolated or with concurrent extraneurologic disease, in 15 adults with high-risk acute lymphoblastic leukemia (ALL), one adult with lymphoid blast crisis of chronic granulocytic leukemia (LBC-CGL), and four adults with poor-prognosis non-Hodgkins lymphoma (NHL). Treatment consisted of ara-C, 3 g/m2 every 12 hours by three-hour infusion for eight doses followed by a second course of four doses on day 21. Remitters received consolidation with monthly courses of HDara-C for four doses. Additional systemic multi-drug reinduction therapy and direct CNS treatment with intrathecal methotrexate (IT MTX) and cranial irradiation (CRT) was administered to the three remitters last treated. Thirteen of 20 patients (65%) achieved complete remission (CR): seven of seven patients with isolated meningeal leukemia and six of 13 patients with concurrent CNS and bone marrow disease. Of the remaining seven patients, five had a complete CSF clearing with persistent marrow disease. In all cases there was prompt resolution of neurologic signs and symptoms. The median duration of CR was 5 months (range 2 to 8 months). The most significant toxicity seen was myelosuppression, which was predictable and manageable. Nonhematologic toxicity was generally acceptable and included moderate nausea and vomiting, diarrhea, drug fever, transient liver dysfunction, and dermatitis. No cases of CNS toxicity occurred. There were no treatment-related deaths. Disease-free survival was limited by marrow relapse, either isolated or with concurrent CNS disease. No instances of isolated meningeal relapse occurred. These results obtained in a poor-risk subset of patients indicate that HDara-C is an effective treatment for the induction of remission in ALL and NHL with meningeal leukemia. Therefore, HDara-C should be considered for inclusion in multiagent consolidation programs for patients at high risk for CNS disease.