Summary
We describe 36 patients with splenic marginal zone lymphoma (SMZL) with transformation (SMZL‐T), including 15 from a series of 84 patients with SMZL diagnosed at the Hospital Clinic of ...Barcelona (HCB) and 21 diagnosed with SMZL‐T in other centres. In the HCB cohort, the cumulative incidence of transformation at 5 years was 15%. Predictors for transformation were cytopenias, hypoalbuminaemia, complex karyotype (CK) and both the Intergruppo Italiano Linfomi (ILL) and simplified Haemoglobin, Platelet count, lactate dehydrogenase (LDH) and extrahilar Lymphadenopathy (HPLL)/ABC scores (P < 0·05). The only independent predictor for transformation in multivariate analysis was CK hazard ratio (HR) 4·025, P = 0·05. Patients with SMZL‐T had a significantly higher risk of death than the remainder (HR 3·89, P < 0·001). Of the 36 patients with SMZL‐T, one developed Hodgkin lymphoma and 35 a diffuse large B‐cell lymphoma, 71% with a non‐germinal centre phenotype. The main features were B symptoms, lymphadenopathy, and high serum LDH. CK was observed in 12/22 (55%) SMZL‐T and fluorescence in situ hybridisation detected abnormalities of MYC proto‐oncogene, basic helix‐loop‐helix transcription factor (MYC), B‐cell leukaemia/lymphoma 2 (BCL2) and/or BCL6 in six of 14 (43%). In all, 21 patients received immunochemotherapy, six chemotherapy, one radiotherapy and three splenectomy. The complete response (CR) rate was 61% and the median survival from transformation was 4·92 years. Predictors for a worse survival in multivariate analysis were high‐risk International Prognostic Index (HR 5·294, P = 0·016) and lack of CR (HR 2·67, P < 0·001).
The treatment of newly diagnosed multiple myeloma has evolved rapidly over the recent years. In younger patients, autologous stem cell transplantation (ASCT) is still considered the standard of care, ...but the availability of new effective drugs with novel mechanisms of action in the last decade has resulted in a new scenario that has caused the role of transplantation itself to be currently undergoing scrutiny.
Maintaining the response of first-line therapy is an important objective in multiple myeloma, where despite intensive therapy followed by ASCT the majority of patients will relapse. In this field, the recent results of different consolidation and maintenance therapies after transplant are very encouraging. These strategies have come to stay and will play an essential role in the next future to improve the prognosis of young patients with newly diagnosed multiple myeloma. Finally, new conditioning regimens will also be tested in the forthcoming years in an attempt to further improve posttransplant responses.
Multiple myeloma ASCT must be integrated within a more global therapeutic approach including new and more effective induction, consolidation, and maintenance approaches. Efforts aimed in the development of more effective and less toxic preparative regimens to further augment disease control are also warranted.
We report data from a prospective, observational study (ZAGAL) evaluating miglustat 100mg three times daily orally. in treatment-naïve patients and patients with type 1 Gaucher Disease (GD1) switched ...from previous enzyme replacement therapy (ERT). Clinical evolution, changes in organ size, blood counts, disease biomarkers, bone marrow infiltration (S-MRI), bone mineral density by broadband ultrasound densitometry (BMD), safety and tolerability annual reports were analysed. Between May 2004 and April 2016, 63 patients received miglustat therapy; 20 (32%) untreated and 43 (68%) switched. At the time of this report 39 patients (14 36% treatment-naïve; 25 64% switch) remain on miglustat. With over 12-year follow-up, hematologic counts, liver and spleen volumes remained stable. In total, 80% of patients achieved current GD1 therapeutic goals. Plasma chitotriosidase activity and CCL-18/PARC concentration showed a trend towards a slight increase. Reductions on S-MRI (p=0.042) with an increase in BMD (p<0.01) were registered. Gastrointestinal disturbances were reported in 25/63 (40%), causing miglustat suspension in 11/63 (17.5%) cases. Thirty-eight patients (60%) experienced a fine hand tremor and two a reversible peripheral neuropathy. Overall, miglustat was effective as a long-term therapy in mild to moderate naïve and ERT stabilized patients. No unexpected safety signals were identified during 12-years follow-up.
•SMZL transformation is associated with genomic complexity and distinct genomic alterations (TNFAIP3, CDKN2A/B, TP53, and 6p+).•KLF2 mutations and complex karyotypes in transformed SMZL confer a ...shorter survival.
Display omitted
The genetic mechanisms associated with splenic marginal zone lymphoma (SMZL) transformation are not well defined. We studied 41 patients with SMZL that eventually underwent large B-cell lymphoma transformation. Tumor material was obtained either only at diagnosis (9 patients), at diagnosis and transformation (18 patients), and only at transformation (14 patients). Samples were categorized in 2 groups: (1) at diagnosis (SMZL, n = 27 samples), and (2) at transformation (SMZL-T, n = 32 samples). Using copy number arrays and a next-generation sequencing custom panel, we identified that the main genomic alterations in SMZL-T involved TNFAIP3, KMT2D, TP53, ARID1A, KLF2, 1q gains, and losses of 9p21.3 (CDKN2A/B) and 7q31-q32. Compared with SMZL, SMZL-T had higher genomic complexity, and higher incidence of TNFAIP3 and TP53 alterations, 9p21.3 (CDKN2A/B) losses, and 6p gains. SMZL and SMZL-T clones arose by divergent evolution from a common altered precursor cell that acquired different genetic alterations in virtually all evaluable cases (92%, 12 of 13 cases). Using whole-genome sequencing of diagnostic and transformation samples in 1 patient, we observed that the SMZL-T sample carried more genomic aberrations than the diagnostic sample, identified a translocation t(14;19)(q32;q13) present in both samples, and detected a focal B2M deletion due to chromothripsis acquired at transformation. Survival analysis showed that KLF2 mutations, complex karyotype, and International Prognostic Index score at transformation were predictive of a shorter survival from transformation (P = .001; P = .042; and P = .007; respectively). In summary, SMZL-T are characterized by higher genomic complexity than SMZL, and characteristic genomic alterations that could represent key players in the transformation event.
Abstract
A bortezomib-containing regimen followed by high-dose therapy and autologous stem cell transplant (ASCT) is considered the standard of care for front-line therapy in younger patients with ...newly diagnosed multiple myeloma (MM). We analyzed the results of ASCT with an intravenous busulfan 9.6 mg/kg and melphalan 140 mg/m2 (ivBUMEL) preparative regimen in 47 patients with newly diagnosed MM who had received bortezomib-based combinations as pre-transplant induction. The overall response rate and complete response after transplant were 100% and 49%, respectively. With a median follow-up of 24.5 months, median overall survival and progression-free survival have not been reached. Mucositis and febrile neutropenia were the most frequent toxicities observed. No case of sinusoidal obstruction syndrome was observed and there was no transplant-related mortality. These results suggest that front-line induction therapy with a bortezomib-based combination followed by ASCT with ivBUMEL is an effective and well-tolerated therapeutic approach for transplant eligible patients with MM.
Abstract 3560
We have previously reported a high response rate with a conditioning regimen consisting of intravenous busulfan (ivBu) and melphalan (Mel) in patients with multiple myeloma (MM) ...undergoing autologous stem cell transplant (ASCT) (Blanes M et al, Leuk Lymphoma 2009). In this case-matched study, we analyze the efficacy and toxicity of ivBuMel as conditioning regimen before ASCT in 51 patients with newly diagnosed MM. Their clinical outcome was compared with that of a control group of 102 pair mates included in the Spanish PETHEMA/GEM2000 study of tandem transplant (control group).
Patients in the control group were transplanted between 2002 and 2005, while patients in the ivBuMel group underwent ASCT between 2005 and 2009. Controls were matched with respect to sex, age, Durie-Salmon and ISS stage at diagnosis, and disease status at transplant. The conditioning regimen comprised iv Bu (3.2 mg/kg in a single daily dose, days -5 to -3) and Mel (140 mg/m2, day -2). Patients in the control group underwent a first ASCT after Mel 200 mg/m2 (Mel 200) in a single dose on day -2 followed in patients failing to achieve a complete response (CR) by a second autologous transplant. The conditioning regimen administered in the second transplant was either Mel 200 or a combination of cyclophosphamide, carmustine, and etoposide.
There were no differences in the hematopoietic recovery and mild or moderate mucositis was the toxicity most frequently observed in both groups of patients. Two (4%) patients died due to transplant-related complications in the ivBuMel group and 5 (5%) in the control group. The CR/near CR (nCR) rate was 51 % in both groups. After median follow-up of 32 and 40.5 months in the ivBuMel and control group, respectively, median progression free survival (PFS) was 37.6 for patients who received ivBuMel and 26.5 months for those in the control group. At 4 years, overall survival and PFS was 65±10% and 42±9% in the ivBuMel and 62±5% and 32± 5% in the control group, respectively (P = NS). For patients achieving CR/nCR after ASCT, the 4-years PFS rate was 52±14% and 40±8% in ivBuMel and control group, respectively (P = 0.3). Finally, in patients achieving partial response or less after transplant, the 4-years PFS rate was 33±12% and 23±6% in ivBuMel and tandem transplant group, respectively (P = 0.3).
Results of this case-matched study suggest that the use of ivBuMel conditioning regimen before ASCT in patients with newly diagnosed MM is associated with low transplant-related morbidity and mortality and a high anti myeloma efficacy that compares favourably with a tandem transplant strategy.
No relevant conflicts of interest to declare.
We evaluated the toxicity and outcome of a conditioning regimen comprising intravenous (iv) busulfan (BU) and melphalan (MEL) in 55 patients (median age, 61 years; range, 34-71) with multiple myeloma ...(MM) undergoing autologous stem-cell transplantation (ASCT). In 49 patients, this was the first ASCT. At transplant, 3 patients were in complete response (CR), 8 in near CR (nCR) and 30 in partial response (PR). The conditioning regimen comprised ivBU (3.2 mg kg in a single daily dose, days −5 to −3) and MEL (140 mg m2, day −2). Mucositis was the most frequent non-hematopoietic toxicity (47 patients). No patient developed sinusoidal occlusive syndrome. Febrile events were observed in 46 patients and were the cause of death in two (3.6%) transplant-related deaths. With a median follow-up of 15 months, 27 patients achieved CR nCR (11 CR) and 21 a PR. The one-year actuarial overall and progression-free survival rates are 96% and 87%, respectively. This ivBU-containing regimen is associated with an acceptable toxicity and a high-response rate.
Abstract 2452
Clinical trials have shown an improved response rate and progression free survival (PFS) among the different treatment options used in the last two decades, specially with rituximab in ...combination with fludarabine and cyclophosphamide. We wished to analyze, in an unselected community based population, the clinical characteristics and efficacy of first line therapy with several treatment options used throughout a ten-year period.
We included 307 patients diagnosed of CLL and requiring first-line treatment between January 2000 and September 2009. Patients were treated at 20 hospitals placed in the Community of Valencia and Murcia and received first-line therapy according to the clinical guidelines of each hospital. PFS was calculated from date of first treatment to date of progression/relapse. We performed a descriptive analysis of clinical and biological features. The survival curves were built with Kaplan-Meier method and compared with the log rank test. Multivariate analysis for response and PFS were performed by logistic and Cox regression methods respectively, using the statistical package SPSS (v15).
Median age at treatment was 67 years (range 28–94) with 58% (n=179) men. 39% (120/305) were in Binet A, 38% (117) in Binet B and 22% (68) in Binet C. 27% (84) were Rai III-IV. B symptoms were present in 25% (77) and fever was a rare symptom 3%. Patients were asymptomatic in 59% (181) of the cases with ECOG performance status 0–1 in 83% (256). Splenomegaly was present in 41% (127) and hepatomegaly only in 8% (24). 42% of the patients (129) had at least three lymph-node areas affected with bulky disease (diameter higher than >5cm) in 10% (32). Median haemoglobin level was 126gr/L (46–169), lymphocyte count 49 x109/L (0,5–613) with lymphocyte doubling time (LDT) <12 months in 43%. LDH was elevated in 34% (95/284) and b2-microglobulin levels in 61% (154/251). CD38 expression was positive in 42% (107/255) and ZAP-70 in 75% (91/122). The overall incidence of trysomy 12, 13q, 11q23 and 17p deletions detected by FISH were 17%, 15%, 12% and 5% respectively. Median follow-up was 33.5 months (0.6–156). First line treatment schedules and treatment response in every group are detailed in table 1.
Patients receiving rituximab (group 3–4, n=73) achieved a significant higher response rate (CR or PR) than patients without rituximab (93% vs 61%). The main clinical variables with prognosis significance in the univariate analysis for PFS were: lymphocyte count (p=0,026, HR 1.002, CI95% (1.000–1.004)); haemoglobin level (p=0,02, HR 0.890, CI95% (0.826–0.958); b2-microglobulin (p=0,002, HR 1.372, CI95% (1.125–1.672)); bulky mass (p=0,055, HR 1.656, CI95% (0.989–2.775)); CD38 expression (p=0,045, HR 1.005, CI95% (1.000–1.011)); p53 deletion (p=0,014, HR 2,231, CI95% (1,180–4,217)) and 11q23 deletion (p=0,03, HR 2,138, CI95% (1,290–3,542)). The median PFS for patients in the different groups were: G1:26.9 months (22.4–31.3), G2 45.5 months (32.7–58.4), G3: not reached, G4: 20.5 months (29.6–47.3), p < 0.0001.
In the multivariate analysis the variables with independent prognostic significance for PFS were: lymphocyte count (p=0.003, HR 1.004, CI 95% (1.001 −1.007)), 17deletion (p=0.01, HR 2.7 CI95% (1.273–5.73)), 11q deletion (p=0.006, HR 2.193 CI95% (1.248–3.852)) and treatment received (G1 as reference): G2 (p=0.005, HR 0.464, CI95% (0.271–0.794)), G3 (p < 0.001, HR 0.179, CI95% (0.083–0.386)), G4 (p=0.223, HR 0.289, CI95% (0.039–2.130)).
In this community based population, treatment with rituximab containing regimens results in a higher global and complete response rate and a longer PFS compared with alquilating agents and purine analogs. Fludarabine containing-schedules also achieved a significant higher response rate than alquilating agents. Rituximab in combination with purine analogs provide the better quality of response. These results confirm the data provided by clinical trials and support their use as front-line treatment.
Terol: ROCHE: Consultancy.
PDF
