Waldenstrom's macroglobulinemia : population based studies of familial aggregation and prognostic factors

Background Waldenstrom’s macroglobulinemia (WM) is a rare lymphoproliferative disorder with a world-wide incidence of 3-4 patients per million persons per year. In Sweden, the incidence was about three times higher, and approximately 100 patients per year are reported to the Swedish Lymphoma Registry (SLR). Our aim was to study the WM population with focus on incidence and survival in relation to clinical prognostic factors and primary therapies (Paper I-II). We also discussed the diagnostic difficulties in patients with non-WM lymphoplasmacytic lymphoma (LPL). In Paper III-IV, we study familial WM from different aspects to better understand underlying pathogenetic factors. Patients and methods The patients in all four studies were collected from SLR. In papers I and II, a total of 1511 patients with WM and non-WM LPL were registered between 2000 and 2014, and medical records were retrieved for 1139 patients (75%). A retrospective review showed that 981 and 33 (after review by haematopathologist) of these patients fulfilled the World Health Organization (WHO) diagnostic criteria for WM and non-WM LPL, respectively. In Paper III and IV, we used SLR and the Northern Lymphoma Registry (NLR) for the years 1997- 2011. We identified 12 families with a family history of WM, IgM monoclonal gammopathy of undetermined significance (MGUS) and/or multiple myeloma (MM). Results In paper I, the overall survival (OS) for WM improved between the two time periods, 2000-2006 and 2007-2014, with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS at the time of diagnosis in asymptomatic patients in no need of therapy were age, poor performance status (PS), haemoglobin ≤115 g/l, and female sex. Elevated lactate dehydrogenase (LDH) level and haemoglobin ≤115 g/l were significant prognostic factors for patients receiving therapy 0-3 months after diagnosis. The level of the IgM monoclonal immunoglobulin (MI) had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival. Paper II describes the differential diagnostic difficulties in non-WM LPL, especially with Marginal Zone Lymphoma (MZL). The non-WM LPL patients had more adverse prognostic factors as elevated LDH, anaemia, and lymphocytosis at diagnosis compared to the patients with WM. Despite this, the OS did not significantly differ between the groups (P = 0.249). The median OS for non-WM LPL was 71 months and the three-year and five-year survival was 71 % and 55%, respectively. The OS and RS were worse for males than females. In Paper III, we showed that age-adjusted incidence in Norrbotten and Västerbotten for WM and non-WM LPL was higher than expected – 17.5 and 14.8 per million person and year, respectively. The corresponding figure for Sweden was 10.5 per million persons per year. Autoimmune diseases or haematological malignancies in the medical history in patients or in their relatives were reported in nine and five of the 12 families, respectively. The relatives showed a high proportion abnormal serum protein electrophoresis (SPE): 12/56 (21%) showed MGUS and 13/56 (25%) showed abnormalities in the immunoglobulin levels (i.e., subnormal levels and poly/oligoclonality). Paper IV describes hyperphosphorylated paratarg 7 (pP-7), a target of 11% of the monoclonal immunoglobulin M (IgM) in WM and MGUS of IgM type, and distribution in Sweden and in familial WM. The frequency of pP-7 seems to be in line or lower in non-familial WM (7.1%) and higher in familial WM (16.7%) in the counties of Norrbotten and Västerbotten than in earlier published studies. Positive analysis for pP-7 was shown up to 10 years before diagnosis of WM. Conclusion We show that in a rare disease such as WM registry studies might bring new knowledge about incidence, disease characteristic, prognostic factors, treatments, and outcome. We also identified aggregation of families with WM in an effort to better understand the underlying pathogenesi

Waldenstrom's macroglobulinemia : population based studies of familial aggregation and prognostic factors

Background Waldenstrom’s macroglobulinemia (WM) is a rare lymphoproliferative disorder with a world-wide incidence of 3-4 patients per million persons per year. In Sweden, the incidence was about three times higher, and approximately 100 patients per year are reported to the Swedish Lymphoma Registry (SLR). Our aim was to study the WM population with focus on incidence and survival in relation to clinical prognostic factors and primary therapies (Paper I-II). We also discussed the diagnostic difficulties in patients with non-WM lymphoplasmacytic lymphoma (LPL). In Paper III-IV, we study familial WM from different aspects to better understand underlying pathogenetic factors. Patients and methods The patients in all four studies were collected from SLR. In papers I and II, a total of 1511 patients with WM and non-WM LPL were registered between 2000 and 2014, and medical records were retrieved for 1139 patients (75%). A retrospective review showed that 981 and 33 (after review by haematopathologist) of these patients fulfilled the World Health Organization (WHO) diagnostic criteria for WM and non-WM LPL, respectively. In Paper III and IV, we used SLR and the Northern Lymphoma Registry (NLR) for the years 1997- 2011. We identified 12 families with a family history of WM, IgM monoclonal gammopathy of undetermined significance (MGUS) and/or multiple myeloma (MM). Results In paper I, the overall survival (OS) for WM improved between the two time periods, 2000-2006 and 2007-2014, with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS at the time of diagnosis in asymptomatic patients in no need of therapy were age, poor performance status (PS), haemoglobin ≤115 g/l, and female sex. Elevated lactate dehydrogenase (LDH) level and haemoglobin ≤115 g/l were significant prognostic factors for patients receiving therapy 0-3 months after diagnosis. The level of the IgM monoclonal immunoglobulin (MI) had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival. Paper II describes the differential diagnostic difficulties in non-WM LPL, especially with Marginal Zone Lymphoma (MZL). The non-WM LPL patients had more adverse prognostic factors as elevated LDH, anaemia, and lymphocytosis at diagnosis compared to the patients with WM. Despite this, the OS did not significantly differ between the groups (P = 0.249). The median OS for non-WM LPL was 71 months and the three-year and five-year survival was 71 % and 55%, respectively. The OS and RS were worse for males than females. In Paper III, we showed that age-adjusted incidence in Norrbotten and Västerbotten for WM and non-WM LPL was higher than expected – 17.5 and 14.8 per million person and year, respectively. The corresponding figure for Sweden was 10.5 per million persons per year. Autoimmune diseases or haematological malignancies in the medical history in patients or in their relatives were reported in nine and five of the 12 families, respectively. The relatives showed a high proportion abnormal serum protein electrophoresis (SPE): 12/56 (21%) showed MGUS and 13/56 (25%) showed abnormalities in the immunoglobulin levels (i.e., subnormal levels and poly/oligoclonality). Paper IV describes hyperphosphorylated paratarg 7 (pP-7), a target of 11% of the monoclonal immunoglobulin M (IgM) in WM and MGUS of IgM type, and distribution in Sweden and in familial WM. The frequency of pP-7 seems to be in line or lower in non-familial WM (7.1%) and higher in familial WM (16.7%) in the counties of Norrbotten and Västerbotten than in earlier published studies. Positive analysis for pP-7 was shown up to 10 years before diagnosis of WM. Conclusion We show that in a rare disease such as WM registry studies might bring new knowledge about incidence, disease characteristic, prognostic factors, treatments, and outcome. We also identified aggregation of families with WM in an effort to better understand the underlying pathogenesi

Clinical characteristic and outcome of lymphoplasmacytic lymphoma of non-Waldenstrom macroglobulinemia type : A Swedish lymphoma registry study

Lymphoplasmacytic lymphoma (LPL) not fulfilling the WHO diagnostic criteria (2017) for Waldenstrom’s macroglobulinemia (WM) (named non-WM LPL) is a rare disease and only a few systematic studies have been published. Here, we present a population-based study of non-WM LPL focusing on diagnostic difficulties, patient characteristics, and outcome. From 1511 patients included in the Swedish Lymphoma Registry 1 Jan 2000 – 31 Dec 2014 with a diagnosis of WM/LPL, we could confirm the diagnosis of non-WM LP in only 33 patients. The median age at diagnosis was 69 years. A paraprotein was found in most (IgG in 54%, IgA in 15%) and 12% of the cases were non-secretory. Compared with the WM patients, the non-WM LPL patients were younger, had more adverse prognostic factors such as elevated LDH, anaemia, and lymphocytosis at diagnosis. In addition, the non-WM LPL patients more often were symptomatic and received treatment at diagnosis. The overall survival (OS) did not significantly differ between the non-WM LPL and WM groups (P = 0.247), with a median survival time of 71 and 96 months, respectively. To conclude, we found differences in clinical features between WM and non-WM LPL, but no difference in survival

Nationwide Assessment of Patient Trajectories in Mantle Cell Lymphoma: The Swedish MCLcomplete Project

Mantle cell lymphoma (MCL) is a B-cell malignancy currently considered incurable. Although some patients obtain prolonged remission after first-line chemoimmunotherapy, many will need several treatment lines. Here, we present a nationwide assessment of treatment strategies, time to progression and survival in MCL. All patients diagnosed with MCL 2006–2018 were identified in the Swedish Lymphoma Register. Information on all lines of therapy was extracted from the medical records. Overall and progression-free survival (OS and PFS) were assessed through August 2021. In total, 1367 patients were included (median age, 71 years) and median follow-up was 6.8 years. Two hundred and one (15%) were managed initially with watch-and-wait, but 1235 (90%) eventually received treatment. The most frequently used first-line regimens were rituximab-bendamustine (BR) (n = 368; 30%) and Nordic MCL2 (n = 342; 28%). During follow-up, 630 patients (46%) experienced relapse/progression and 546 (40%) received second-line treatment. The most frequently used second-line regimen was BR (n = 185; 34%) but otherwise a wide variety of second-line treatments were used. Further, 382 and 228 patients experienced a second or third relapse/progression, respectively. Median PFS after first (PFS-1), second (PFS-2), third (PFS-3), and fourth (PFS-4) treatment lines was 29.4, 8.9, 4.3, and 2.7 months. Patients with early progression, defined as a PFS-1 <24 months, had an inferior median OS of 13 versus 37 months in patients with later relapse. For patients treated with frontline BR, however, time to relapse had no impact on later outcome. By use of nationwide population-based data, we provide important benchmarks for future studies of all treatment lines in MCL

Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS: Results from the nordic NMDSG08A phase II trial

This prospective phase II study evaluated the efficacy of azacitidine (Aza)+erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo+granulocyte colony stimulation factors for >8 weeks and a transfusion need of greater than or equal to4 units over 8 weeks were included. Aza 75 mg m−2 d−1, 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received greater than or equal toone cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza+Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n=3) and DNMT3A (n=4) were only observed in non-responders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations