Lara Malerba

BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients

We designed a phase 1-2 study to evaluate the safety and the efficacy of increasing doses of bendamustine (160 mg/m², 180 mg/m², and 200 mg/m² given on days -7 and -6) coupled with fixed doses of etoposide, cytarabine, and melphalan (BeEAM regimen) as the conditioning regimen to autologous stem cell transplantation for resistant/relapsed lymphoma patients. Forty-three patients (median age, 47 years) with non-Hodgkin (n = 28) or Hodgkin (n = 15) lymphoma were consecutively treated. Nine patients entered the phase 1 study; no patients experienced a dose-limiting toxicity. Thirty-four additional patients were then treated in the phase 2. A median number of 6 × 10⁶ CD34(+) cells/kg (range, 2.4-15.5) were reinfused. All patients engrafted, with a median time to absolute neutrophil count > 0.5 × 10⁹/L of 10 days. The 100-day transplantation-related mortality was 0%. After a median follow-up of 18 months, 35 of 43 patients (81%) are in complete remission, whereas 6 of 43 relapsed and 2 of 43 did not respond. Disease type (non-Hodgkin lymphomas vs Hodgkin disease) and disease status at transplantation (chemosensitive vs chemoresistant) significantly influenced DFS (P = .01; P = .007). Remarkably, 4 of 43 (9%) patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell transplantation. In conclusion, the new BeEAM regimen is safe and effective for heavily pretreated lymphoma patients. The study was registered at European Medicines Agency (EudraCT number 2008-002736-15).

Common and rare side-effects of low-dose thalidomide in multiple myeloma: focus on the dose-minimizing peripheral neuropathy

Objectives:  Thalidomide has demonstrated a remarkable efficacy in the treatment of multiple myeloma but its use may cause several toxicities. We have investigated the common and rare side‐effects, especially analysing peripheral neuropathy, in order to optimise the thalidomide dose for minimizing this harmful side‐effect.

Efficacy and tolerability of bendamustine, bortezomib and dexamethasone in patients with relapsed-refractory multiple myeloma: a phase II study

Bendamustine demonstrated synergistic efficacy with bortezomib against multiple myeloma (MM) cells in vitro and seems an effective treatment for relapsed-refractory MM (rrMM). This phase II study evaluated bendamustine plus bortezomib and dexamethasone (BVD) administered over six 28-day cycles and then every 56 days for six further cycles in patients with rrMM treated with ⩽4 prior therapies and not refractory to bortezomib. The primary study end point was the overall response rate after four cycles. In total, 75 patients were enrolled, of median age 68 years. All patients had received targeted agents, 83% had 1–2 prior therapies and 33% were refractory to the last treatment. The response rate⩾partial response (PR) was 71.5% (16% complete response, 18.5% very good PR, 37% partial remission). At 12 months of follow-up, median time-to-progression (TTP) was 16.5 months and 1-year overall survival was 78%. According to Cox regression analysis, only prior therapy with bortezomib plus lenalidomide significantly reduced TTP (9 vs 17 months; hazard ratio=4.5; P=0.005). The main severe side effects were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), neuropathy (8%) and gastrointestinal and cardiovascular events (both 6.5%). The BVD regimen is feasible, effective and well-tolerated in difficult-to-treat patients with rrMM.

Bendamustine, etoposide, cytarabine, melphalan, and autologous stem cell rescue produce a 72% 3-year PFS in resistant lymphoma

To the editor: Based on the results of the PARMA and CORAL studies, high-dose chemotherapy (HDT) followed by autologous stem cell rescue has become the standard of care for patients with relapsed, chemosensitive aggressive non-Hodgkin lymphoma (NHL).[1][1],[2][2] Moreover, HDT/autologous stem cell

Cyclophosphamide, pegylated liposomal doxorubicin, vincristine and prednisone (CDOP) plus rituximab is effective and well tolerated in poor performance status elderly patients with non-Hodgkin's lymphoma

Lymphomas in elderly patients require special attention, not only for possible important co-morbidities and poor performance status, but also for diminished organ functions and altered drug metabolism, which modify the pharmacokinetics of the treatment [1]. Thus, first-line elderly non-Hodgkin’s lymphoma (NHL) patients are frequently treated with a consequent dose reduction [2,3]. Similarly, the treatment outcome of salvage therapy for relapsed/ refractory NHL patients is limited by multidrug resistance, low performance status and the high toxicity of secondand third-line regimens. Anthracycline-based regimens are extremely effective in NHL; the main disadvantage is cardiotoxicity. Pegylated liposomal doxorubicin has been shown to determine lower toxicity if compared with conventional doxorubicin, while having similar efficacy in patients with Kaposi’s sarcoma and solid tumors. Due to the prolonged half-life (nearly 43 h), it offers the opportunity of obtaining prolonged exposure of tumor cells to active concentrations, with possible effects on the disease. A recent study concluded that an improvement in the survival of elderly patients with lymphoma is related to an optimized toxicity chemotherapy schedule [4,5]. In addition, cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) plus rituximab has been demonstrated to be superior to CHOP alone in elderly patients with diffuse large cell lymphoma [6,7]. We thus tested the safety and efficacy of a regimen [cyclophosphamide, pegylated liposomal doxorubicin, vincristine and prednisone (CDOP) plus rituximab] using a pegylated liposomal doxorubicin instead of conventional doxorubicin, in order to reduce the toxic profile and preserve the dose intensity, administered as follows: day 1, cyclophosphamide 750 mg/m, pegylated liposomal doxorubicin (Caelyx, Schering Plough S.A., Italy) 40 mg/m, vincristine 1.4 mg/m, prednisone 100 mg p.o. days 1 – 5, rituximab 375 mg/ m on day 15 of every cycle; granulocyte colonystimulating factor (G-CSF) from day 10 to day 14. Therapy was repeated every 21 days for 6 cycles. Complete and partial remission were assessed as the overall response. Toxicity was evaluated according to the WHO criteria. Thirteen patients were treated (Table I); 12 (92%) completed the 6 courses and were assessable for response (Table II). A dose reduction (25%) was carried out in 2 cases (1 frail, 1 relapsed-refractory), due to their extremely altered clinical condition. Seven patients (53%) obtained complete remission, 5 (31%) partial remission, for an overall response rate of 84%. No major toxicity (WHO grade III/IV) occurred. Only 1 patient delayed therapy for grade II hematological toxicity. After a median follow-up of 18 months (range 8 – 22 months), 7 patients are in continuous complete remission (53%), 3 (23%) in partial remission, 1 in stable disease, whereas only 2 patients progressed. In our opinion, one of the reasons for the high overall response rate (84%) and of the maintenance of the response, even in this category of very fragile patients, is the respect of the doses, as well as of the

Pegfilgrastim effectively mobilizes PBSC in a poor mobilizer multiple myeloma patient.

Abstract:  Studies performed on mice and healthy human volunteers have shown that a single dose of pegfilgrastim (Peg‐GCSF) is effective in stimulating peripheral blood stem cells (PBSC) mobilization. This prompted us to try the stimulation with pegfilgrastim in a patient previously non‐mobilizing with a combination of chemotherapy and filgrastim. In December 2003, a 65‐yr‐old man was diagnosed as having stage III A IgG/k multiple myeloma. He received three courses of polichemotherapy (DC‐IE) obtaining a stable response. Afterwards, the patient was treated with high‐dose cyclophosphamide (CPM; 7 g/sqm) plus daily 10 mcg/kg filgrastim in order to mobilize PBSC, without success. After 2 months off therapy, the disease progressed and the patient received alternate cycles VAD (vincristine, dexamethasone, adriblastine)/high‐dose dexamethasone. A second attempt to mobilize PBSC, using daily 10 mcg/kg filgrastim after the second and third VAD cycle, failed. In a further attempt to mobilize PBSC, we administered a single dose of 12 mg pegfilgrastim on day 5 after a fourth VAD course. Daily evaluation of circulatory CD34+ cells was started from day 8 after the end of chemotherapy. On day +10 postchemotherapy the CD34+ cell count was 24/μL and two aphaeresis were performed, harvesting 1.6 × 106 and 0.89 × 106 CD34+ cells/kg respectively (total 2.49 × 106 cells/kg). The only side effect was moderate skeletal pain. The patient underwent successful transplantation. The median times necessary to recover 0.5 × 109 PMN/L and 20 × 109 platelets/L after PBSC reinfusion were 9 and 12 d respectively. The patient did not need red blood cell or platelet transfusions. He experienced a sustained engraftment and maintains complete remission 9 months after the reinfusion. In conclusion, a single dose of pegfilgrastim was able to mobilize a sufficient number of CD34+ in a multiple myeloma patient not responsive to two previous attempts with high or standard dose chemotherapy followed by filgrastim. This approach, if confirmed on larger series and other diseases, could open new opportunities in stem cell mobilization for poor or non‐mobilizers.

Comparison of two regimens for the treatment of elderly patients with acute lymphoblastic leukaemia (ALL).

Acute lymphoblastic leukemia (ALL) represents a rare malignancy in the elderly and few authors have specifically focused on the treatment of ALL in this setting. We recently published the results of a prospective phase II study comprising an induction therapy with vincristine, Daunoxome and dexamethasone (VDXD) given to 15 patients aged ⩾̸ 60 years. Here, we update the results after enrolling 17 patients, and we compare these with the results obtained in 17 elderly patients treated according to the GIMEMA ALL 0288 protocol. With the VDXD combination, elderly ALL had a higher CR rate (76.5%) than with the 0288 protocol (41%), and it was likely due to both lower induction mortality (17.5% vs. 35%) and a less resistant disease (6% vs. 24%). Infectious complications were more frequent with the VDXD combination whereas non-hematological side effects were comparable. Despite the similar DFS obtained with the two induction treatments, median EFS (3.9 months with 0288 vs. 12.8 with VDXD; p = 0.0486) and OS (4.5 vs. 21 months; p = 0.0239) were significantly higher with the VDXD regimen. In elderly ALL patients the administration of high-dose daunorubicin as a liposomal compound is feasible and seems able to improve CR rate, EFS and OS without increase in toxicity.

An observational study of once weekly intravenous ganciclovir as CMV prophylaxis in heavily pre-treated chronic lymphocytic leukemia patients receiving subcutaneous alemtuzumab

Fifteen consecutive resistant/relapsed chronic lymphocytic leukemia (CLL) patients (median age: 65 years) received alemtuzumab for 16 consecutive weeks. All patients had negative CMV anti genemia at baseline. Five patients received oral acyclovir 800 mg twice a day for CMV prophylaxis and 10 patients got intravenous (iv) ganciclovir 7.5 mg/kg once a week. A total of five CMV reactivations occurred, four in the acyclovir and one in the ganciclovir prophylaxis group. Alemtuzumab was then discontinued and all patients were treated with iv ganciclovir 7.5 mg/kg per day. All patients achieved negative CMV anti genemia after a median of 15 days of therapy. Weekly iv ganciclovir prophylaxis and alemtuzumab treatment were then restarted without any further CMV reactivations. In conclusion, weekly iv ganciclovir appears feasible and effective in preventing CMV reactivation and disease in this setting of high-risk immunocompromised patients, allowing an easier management of a therapy otherwise difficult to be routinely used.

Infectious Complications in Adult Acute Lymphoblastic Leukemia (ALL): Experience at One Single Center

Literature provides no specific data concerning the type and the risk factors for infection in adult patients with acute lymphoblastic leukemia (ALL). We retrospectively analyzed 97 adult ALL patients who underwent conventional chemotherapy during a 14-year period with the aim to assess the incidence and the factors affecting onset and outcome of infections. We found that during induction therapy 50% of patients developed infection, mainly caused by gram-negative bacteria and with a mortality rate of 11%. In multivariate analysis age > 60 years was significantly associated with more infections (P = 0.04) and higher related mortality (P = 0.03). Moreover, in 22% of patients infectious complications occurred during consolidation or maintenance therapy. Mortality rate of these infections, mostly due to opportunistic pathogens, was 16%. Factors affecting mortality was the cumulative dose of methylprednisolone given during induction therapy ( < or = 2600 mg = 31% vs. > 2600 mg = 69%; P = 0.03). Among neutropenic patients, adults with ALL represent a peculiar population since they frequently develop gram negative infections during induction and opportunistic infections during post-remission treatments. Advanced age and high-dose methylprednisolone result the major risk factors for infection related mortality in the former therapeutic phase and in the latter one, respectively.

Gemcitabine Alone or Combined with Cisplatin in Relapsed or Refractory Multiple Myeloma

Gemcitabine is a pyrimidine nucleoside analog with antitumor activity against solid tumor malignancies and leukemia. We evaluated its activity as a single agent and combining it with cisplatin in relapsed-refractory multiple myeloma (MM). Sixteen patients with advanced MM received intravenous gemcitabine 1250 mg/mq (days 1, 8 and 15) as a single agent for a total of 3 monthly courses. The responders received another three courses, and the non-responders received three courses of gemcitabine 1000 mg/mq (days 1, 8 and 15) plus cisplatin 80 mg/mq (day 1). No grade 4 hematological toxicity was seen after gemcitabine treatment, whereas ≥ 3 grade neutropenia and thrombocytopenia were seen in 21 and 13% of the gemcitabine-cisplatin infusions, respectively. Non-hematological toxicity was negligible for both the regimens. After three courses of gemcitabine as a single agent, the response rate was 31% (1 complete response, 1 partial response and 3 minimal response). Eight patients (50%) achieved stable disease and 3 (19%) had disease progression. Ten patients received gemcitabine-cisplatin and were evaluable for the response. Two patients progressed, four maintained stable disease whereas four patients, unresponsive to gemcitabine, obtained a response (3 partial response and 1 minimal response). With a median follow-up of 13 months (range 8-17.5), 7 patients (44%) died, 5 (31%) had disease progression, 1 (6%) relapsed, 1 was still in partial response (+11 months) and 2 (13%) had a stable disease. Median time to treatment failure (TTF) was 8 months (CI 95%: 7.6-8.4) and median overall survival (OS) was 16 months (CI95%: 10-22). These results showed that gemcitabine and gemcitabine-cisplatin were feasible regimens and well tolerated in advanced relapsed-refractory MM. The response rates, the TTF and OS were similar to other salvage chemotherapy regimens; nevertheless, the quality of response was modest particularly after gemcitabine alone. Better results might be obtained combining gemcitabine with other chemotherapy compounds or with biologically based therapies.