Sara Barulli

Long-term experience with low-dose interferon-α and PUVA in the management of early mycosis fungoides

Abstract:  Objectives: Combined high‐dose Interferon‐α and psoralen plus ultraviolet A irradiation (PUVA) have been reported to be effective in the treatment of early mycosis fungoides (MF); however, our study is the first controlled prospective study in the literature exploring the activity and tolerability of the combination with low dosages and evaluating further clinical outcome of early‐MF patients. Methods: We carried out a multicentric prospective Phase II clinical study on 89 patients with early‐stage IA to IIA MF treated for 14 months with low‐dose IFN‐α2b (6–18 MU/wk) and PUVA. Treatment success was analysed in terms of freedom from treatment failure. Results and conclusions: Complete remission (CR) was achieved in 84% and an overall response rate in 98% of cases: six‐month CR was associated with a non‐confluent skin infiltrate at histology (P = 0.044) and 14‐month CR with high epidermal CD1a+ dendritic‐cell density (P = 0.030). The combination protocol was successfully tolerated and the most common reason of ‘failure’ was related to relapse and not to toxicity. Sustained remissions were achieved in 20% of patients. High CD8+ lymphoid T‐cell density was associated with a lower relapse rate (P = 0.002). We think that our combination therapy can be considered an alternative approach compared with other modalities. Good immunological host surveillance in the skin lesions seems to be an optimal basis for the therapeutic success.

R-COMP 21 for frail elderly patients with aggressive B-cell non-Hodgkin lymphoma: A pilot study

We evaluated the toxicity and efficacy of nonpegylated liposomal doxorubicin (Myocet®) when substituted for conventional doxorubicin in the CHOP-21 regimen in the treatment of frail elderly patients with aggressive non-Hodgkin lymphoma. Twenty frail patients (median age, 73 years), as defined by Balducci et al., with diffuse large B cell or grade IIIb follicular lymphoma, either at diagnosis (15 patients) or relapsed (five patients), were prospectively enrolled. Nine out of 20 (45%) had a World Health Organisation (WHO) performance status ≥2. Fifteen out of 20 patients (75%) had an International Prognostic Index (IPI) score ≥3. Thirteen out of 20 (65%) evaluable patients obtained a complete response. Five additional patients (25%) achieved a partial response. With a median follow-up of 24 months (range 18–27), 15/18 responding patients (83%) are alive and disease free, as well as 3/18 are alive with active disease. Toxicity was mainly hematological with grade 3/4 neutropenia in 26% of cycles and febrile neutropenia in 5%. However, 3/20 patients presented a grade III–IV WHO toxicity (one fatal pulmonary embolism, one congestive, and one ischemic heart failure) while receiving R-COMP chemotherapy. In conclusion, R-COMP-21 is an effective regimen with promising response rates for frail and elderly patients with aggressive non-Hodgkin lymphoma.

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

High-dose therapy followed by stem cell transplantation in Hodgkin’s lymphoma: past and future

Hodgkin’s lymphoma (HL) has been a fascinating challenge for physicians and investigators since its recognition during the 19th century. However, many questions still remain unanswered. One issue regards high-dose therapy followed by autologous stem cell transplantation (ASCT), which has yet to find its place among several guidelines. Other topics are still controversial with respect to transplantation for HL, including its role for newly diagnosed patients with advanced stage disease, the optimal timing of transplantation, the best conditioning regimen and the role of allogeneic/haploidentical SCT. Moreover, the potential use of localized radiotherapy or immunologic methods to decrease post-transplant recurrence, the role of novel agents such as brentuximab vedotin and their positioning in the treatment algorithm of resistant/relapsed HL patients, either before transplant to boost salvage therapy or after transplant as consolidation/maintenance, are burning questions without an answer. In this review, the authors try to give an answer to some of these dilemmas.

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.

Advancement in high dose therapy and autologous stem cell rescue in lymphoma

Although advanced stage aggressive non-Hodgkins lymphomas and Hodgkins disease are thought to be chemotherapy-responsive cancers, a considerable number of patients either relapse or never attain a remission. High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is often the only possibility of cure for most of these patients. However, many controversial issues still remain with respect to HDT/ASCT for lymphomas, including its role for, the optimal timing of transplantation, the best conditioning regimen and the potential use of localized radiotherapy or immunologic methods to decrease post-transplant recurrence. Recently, mainly due to the unavailability of carmustine, several novel conditioning protocols have been clinically developed, with the aim of improving the overall outcome by enhancing the anti-lymphoma effect and, at the same time, by reducing short and long-term toxicity. Furthermore, the better safety profiles of novel approaches would definitively allow patients aged more than 65-70 years to benefit from this therapeutic option. In this review, we will briefly discuss the most relevant and recent data available regarding HDT/ASCT in lymphomas.

Long term outcome of Ph+ CML patients achieving complete cytogenetic remission with interferon based therapy moving from interferon to imatinib era

Interferon α (IFNα) prolongs survival of CML patients achieving CCyR and potentially synergizes with TKIs. We report on the molecular status and long term outcome of 121 patients who were treated in Italy between 1986 and 2000 with IFNα based therapy and who obtained CCyR. After a median follow up of 16.5 years, 74 (61%) patients were switched to standard imatinib: 48 (65%) lost the CCyR on IFNα, and 36 (75%) are alive and in CCyR; 26 (35%) were switched to imatinib when they were still in CCyR on IFNα, and all 26 are alive and in CCyR. Forty‐seven patients (39%) were never switched to imatinib: 24 (51%) continued and 23 (49%) discontinued IFNα, respectively, and 39/47 (83%) are alive and in CCyR. At last follow‐up, the BCR‐ABL transcripts level was available in 96/101 living patients (95%) The BCR‐ABL:ABL ratio was between 0.1 and 0.01% (MR3.0) in 17%, and less than 0.01% (MR4.0) in 81% of patients. No patient was completely molecular negative (MR4.5 or MR5.0). The OS at 10 and 20 years is 92 and 84%, respectively. This study confirms that CCyR achieved with IFNα and maintained with or without imatinib or any other therapy significantly correlates with long term survival in CML patients who mostly have MR4.0. Complete molecular response (MR4.5 or MR5.0) seems to be unnecessary for such a long survival. This study further supports development of studies testing the clinical effect of the combinations of TKIs with IFNα. Am. J. Hematol. 89:119–124, 2014.

Mini-ICE effectively mobilises peripheral blood stem cells after fludarabine-based regimens in acute myeloid leukaemia

Fludarabine‐based cycles severely impair mobilisation and collection of peripheral blood stem cells (PBSC) in acute myeloid leukaemia (AML). In an effort of reversing this side‐effect, we studied the action on mobilisation and collection of PBSC of a low‐dose regimen: 5‐d Mini‐ICE (oral idarubicin and etoposide; subcutaneous cytosine arabinoside) administered after fludarabine‐based regimens in seven adult AML patients. Leukapheresis were started when the CD34+ cell count was more than 10/μL. The median number of harvested CD34+ cells was 8.1 × 106/kg (range 3.08–15.2). All the patients were successfully submitted to PBSC transplantation. Median times to neutrophil and platelet recovery were rapid with a normal transfusional support. We suggest that the Mini‐ICE programme is feasible, well tolerated and effective in terms of PBSC mobilisation and collection in low‐yield AML patients previously treated with fludarabine. It is well known that a negative effect on stem cell mobilisation and harvest is observed not only after fludarabine administration in AML or low‐grade lymphomas, but also after cycles based on different agents, such as thalidomide in multiple myeloma. This preliminary experience, if confirmed on larger series and/or other haematological malignancies, could open new opportunities to perform autologous PBSC transplantation in heavily pretreated cases, allowing a full source of therapeutic options before the start of the mobilisation process.

Complete Clearance of Ph+ Metaphases after 3 Months Is a Very Early Indicator of Good Response to Imatinib as Front-Line Treatment in Chronic Myelogenous Leukemia

Aim: To address the incidence and the prognostic role of a very early standard complete cytogenetic response (CCyR) or all Ph– metaphases (MET–, when <20 cells were evaluable). Methods: We revised 182 chronic phase chronic myelogenous leukemia patients treated with frontline imatinib (IM) at two institutions from June 2002 to June 2011. Results: After 3 months of treatment, 138 patients (75.8%) achieved CCyR/MET– while 44 patients (24.2%) still presented Ph+ metaphases (MET+) (<33%, 24 patients; ≥33%, 20 patients). On univariate analysis, palpable spleen enlargement (p < 0.001), WBC count >100.0 × 109/l at onset (p < 0.001), and male gender (p = 0.019) had a negative impact on achievement of CCyR/MET– at 3 months. Among patients with CCyR/MET– after 3 months, there were 15 failures (10.8%) compared to 21 (47.7%) among patients with MET+ (p < 0.001). The 5-year overall survival was 97.0% in patients CCyR/MET– at 3 months and 91.8% in patients MET+ at 3 months (p = 0.277); the 5-year progression-free survival was 88.2% in patients CCyR/MET– at 3 months and 48.4% in patients MET+ at 3 months (p < 0.001). Conclusions: The achievement of CCyR/MET– at 3 months seems to have prognostic relevance and could be a very early and useful indicator of an excellent response to IM beyond European LeukemiaNet guidelines.

Assessment of the interlaboratory variability and robustness of JAK2V617F mutation assays: A study involving a consortium of 19 Italian laboratories

To date, a plenty of techniques for the detection of JAK2V617F is used over different laboratories, with substantial differences in specificity and sensitivity. Therefore, to provide reliable and comparable results, the standardization of molecular techniques is mandatory. A network of 19 centers was established to 1) evaluate the inter- and intra-laboratory variability in JAK2V617F quantification, 2) identify the most robust assay for the standardization of the molecular test and 3) allow consistent interpretation of individual patient analysis results. The study was conceived in 3 different rounds, in which all centers had to blindly test DNA samples with different JAK2V617F allele burden (AB) using both quantitative and qualitative assays. The positivity of samples with an AB < 1% was not detected by qualitative assays. Conversely, laboratories performing the quantitative approach were able to determine the expected JAK2V617F AB. Quantitative results were reliable across all mutation loads with moderate variability at low AB (0.1 and 1%; CV = 0.46 and 0.77, respectively). Remarkably, all laboratories clearly distinguished between the 0.1 and 1% mutated samples. In conclusion, a qualitative approach is not sensitive enough to detect the JAK2V617F mutation, especially at low AB. On the contrary, the ipsogen JAK2 MutaQuant CE-IVD kit resulted in a high, efficient and sensitive quantification detection of all mutation loads. This study sets the basis for the standardization of molecular techniques for JAK2V617F determination, which will require the employment of approved operating procedures and the use of certificated standards, such as the recent WHO 1st International Reference Panel for Genomic JAK2V617F.