Impact of the presence and number of chromosomal abnormalities on the clinical outcome in Waldenström Macroglobulinemia: a monocentric experience

doi:10.21203/rs.3.rs-3937670/v1

The prognostic and predictive role of specific gene mutations in Waldenström Macroglobulinemia (WM) is well-ascertained whereas the clinical impact of chromosome aberrations is far less known. Recent work has provided initial evidence for an adverse prognostic impact of some aberrations, such as del(6q), while other studies suggest a possible relationship between some clinical features (e.g. advanced age and/or inflammatory status) and specific cytogenetic abnormalities. To add to the still limited knowledge on WM cytogenetics and its clinical implications, we herein report our experience in a cohort of WM patients across 23 years. Based on our retrospective study, we found that abnormal karyotype was more represented in older patients and maintained a statistically significant independence from other molecular, clinical, and biological features related to WM. The presence and the number of cytogenetic aberrations correlated with inferior overall and progression-free survival outcomes regardless of the type of single chromosome aberration. Our data suggests that the role of the altered karyotype deserves to be better clarified specially in elderly WM patients, in whom underlying cytogenetic characteristics and disease biology appear to be characterized by a higher degree of complexity.

Waldenstrom Macroglobulinemia

Cytogenetics

Non-Hodgkin Lymphoma

Chromosomal abnormalities

Waldenström Macroglobulinemia (WM) is a rare indolent non-Hodgkin B cell lymphoma.^1,2 Recently, clinical research has attempted to identify whether the most frequent molecular alterations associated with the disease, i.e. MYD88 and CXCR4 mutations, may have a prognostic and/or a predictive role.^3,4 Other studies have investigated the impact of the underlying cytogenetic alterations on survival outcomes, especially with regards to some aberrations such as deletion of long arm of the chromosome 6 (6q-), or deletion of the short arm of the chromosome 17 (17p-).⁵ A positive correlation between the presence of 6q- and the inflammatory form of WM has been recently described.⁶ Furthermore, there seems to be a difference in terms of the number of chromosomal alterations between younger and very elderly WM patients.⁷

Differently from other B-cell malignancies, the role of cytogenetics in WM has been investigated in few studies. The work by the FILO group, one with the largest sample size reported, demonstrated the independent prognostic value of TP53 abnormalities and high-complex karyotype (≥ 5 chromosome aberrations) in determining a shorter progression free survival (PFS) in WM.^8,9,10

In the present work, we retrospectively revised the cytogenetic data of WM patients collected between 2000 and 2023 in our institution, an academic center with experience on the treatment of this disease. The aim of this study was to assess potential correlations between cytogenetics aberrations and specific clinical and biochemical features (age, disease burden, inflammatory form, renal disorder). In addition, we tested the hypothesis that the numerosity of the cytogenetic alterations could have a prognostic role, therefore affecting survival outcomes, independently from the impact of single, specific cytogenetic abnormalities.

Statistical analysis

Clinical records of WM patients followed between 2000–2023 at the Hematology Unit, University of Padova, Italy have been used to collect data according to the protocol (4089/AO/17) approved by the Ethic Committee of the Azienda Ospedale-Università di Padova.

Clinical, biochemical, molecular and cytogenetic findings obtained at diagnosis have been analyzed. Continuous variables were described by median (interquartile range, IQR) while categorical ones were described by frequency (percentage). Continuous variables were compared with the Mann-Whitney U test, categorical ones were compared with the Chi-square test or the Fisher’s exact test, as appropriate. Survival outcomes considered were overall survival (OS) and progression free survival (PFS). OS was defined as the time from diagnosis to death from any cause while PFS as the time from diagnosis to progression or death from any cause. The impact of variables on survival outcomes (OS, PFS) was investigated with the Cox proportional hazard regression model, by univariate analysis in different subgroups. Results were reported as hazard ratios (HR) and 95% confidence intervals. Missing data were accurately excluded from the analysis. Survival curves were built with the Kaplan-Meier method and compared by the log-rank test. Statistical significance was considered for p-value < 0.05. Statistical analysis was performed on RStudio version 2022.07.2.

Chromosome banding and molecular analyses

Chromosome banding analysis (CBA) was performed on bone marrow aspirate after a 72h stimulation with 500 µM CpG ODN DSP30 mitogen (Roche, Risch, CH) + 20 U/mL interleukin-2 (IL-2) (Roche). After overnight exposure with 1 µg of KaryoMax® Colcemid® Solution (Life technologies Corporation, Grand Island, NY, USA), cells were harvested by adding 0.075 M KCL hypotonic solution and incubated for 30’ at room temperature, followed by three times fixation with Carnoy’s solution. Wright’s stain was diluted in Söerensen’s Buffer (0.06 M/l Na2HPO4/0.06 M/l KH2PO4) for G-Banding analysis. The slides were analyzed using the Metafer automated acquisition system (MetaSystems s.r.l., Milan, Italy), and the karyotype was described after the analysis of at least 25 metaphases in accordance with international guidelines (ISCN2020).¹¹

Complex karyotype (CK) and high complex karyotype were defined respectively as the presence of 3 or more and 5 or more clonal cytogenetic abnormalities.

To detect MYD88 L265P mutation on bone marrow aspirate, a highly sensitive allele-specific PCR (AS-PCR) was used. Two non-competitive PCRs were run to identify the wild-type and mutated sequences by using 2 forward primers, one specific for the wild-type allele and the second one specific for the mutated.¹²

To investigate CXCR4 mutations on bone marrow aspirate we used 2 allele-specific PCR, one for the c.1013C > G mutation and another for the c.1013C > A and we performed sequence analysis of exon 2 to identify other non-sense or frameshift mutations.^13,14

A total number of 85 out of 207 newly diagnosed WM patients was successfully karyotyped by chromosome banding between 2000 and 2023. The median follow-up period for the entire cohort was 51 (19–81) months.

The cohort of patients that was studied comprised 64 (75.3%) out of the initial 85, due to the loss of 13 patients during follow up, lack of data in 6 cases, and the exclusion of other 2 patients because of cytogenetics being performed after the diagnosis (Table 1). In terms of CBA, 30 out of 64 patients (46.9%) showed an abnormal karyotype with a single chromosome change in 17/30 (56.6%) cases, two abnormalities in 7/30 (23.3%) patients and a CK in 6/30 (20%) patients. Only 2 patients exhibited a karyotype with more than 5 clonal chromosomal aberrations (high-CK). Considering the type of aberrations, structural abnormalities were detected in 13/30 (43.3%) of cases followed by numerical changes in 11/30 (36.6%). Both structural and numerical aberrations were found in a minority of cases, specifically in 6 of 30 (20.0%).

In line with other previously published studies, the most frequent aberration was the deletion of the long arm of chromosome 6 (6q-) in 7/30 (23.3%) patients, followed by the trisomy of the chromosome 3 (+ 3) in 7/30 (23.3%) patients and the deletion of long arm of the chromosome 11 (11q-) detected in 4/30 (13.3%) cases. The loss of Y chromosome (-Y) similarly to the trisomy of the chromosome 18 (+ 18) and to the trisomy of the chromosome 12 (+ 12) was described in 4/30 (13.3%) patients for each reported aberration. (Table 2).

Table 1

Baseline characteristics of WM patients with normal and abnormal karyotype
	Normal karyotype n = 34	Abnormal karyotype n = 30	P value
Age, years, median (IQR)	65 (58–70)	72 (66–82)	0.003
CIRS > 6, n (%)	15/27 (0.56)	16/28 (0.57)	1.00
ECOG PS ≥ 2, n (%)	5/28 (0.18)	2/26 (0.08)	0.42
Hb ≤ 115 g/L, n (%)	13/34 (0.38)	10/30 (0.30)	0.68
PLTs ≤ 100 x 10⁹/L, n (%)	4/34 (0.12)	0/30 (0.00)	0.11
β2-microglobulin > 3 mg/L, n (%)	14/19 (0.74)	10/13 (0.77)	0.84
MC IgM, g/L, median (IQR)	12.00 (6.90-20.39)	14.65 (8.51–25.75)	0.24
CRP, mg/L, median (IQR)	4.80 (2.90–35.00)	5.37 (2.90–10.00)	0.80
BM infiltration, %, median (IQR)	55 (19–76)	77 (65–98)	0.79
Creatinine, micromol/L, median (IQR)	75 (63–88)	77 (65–98)	0.79
MYD88^L265P, n (%)	26/31 (0.84)	24/27 (0.89)	0.58
CXCR4 mut, n (%)	5/17 (0.29)	2/15 (0.13)	0.40
IPSSWM Low, n (%) Intermediate, n (%) High, n (%)	14/34 (0.42) 10/34 (0.29) 10/34 (0.29)	6/30 (0.20) 11/30 (0.37) 13/30 (0.43)	0.07
Second cancer, n (%)	3/34 (0.88)	10/30 (0.30)	0.03
1st line treatment, n (%)	26/34 (0.76)	18/30 (0.60)	0.15
Major response rate, n (%)	16/26 (0.62)	7/18 (0.39)	0.13
2nd or more treatment lines, n (%)	8/34 (0.24)	9/30 (0.30)	0.56

BM: Bone marrow; CIRS: Cumulative Illness Rating Scale; CRP: C-reactive protein ECOG-PS: Eastern Cooperative Oncology Group Performance Status; Hb: Hemoglobin; IPSSWM: International Prognostic Scoring System on Waldenström Macroglobulinemia; IQR: Interquartile range; MC: Monoclonal Component

In the abnormal karyotype subgroup, we observed a higher prevalence of secondary cancers (30.00% vs 8.82%, p = 0.03) and a trend towards a higher IPSSWM score (43.00% vs 29.00%, p = 0.07).

When comparing WM patients with and without cytogenetic abnormalities, no significant correlation was observed between the presence of cytogenetic abnormalities and disease burden, renal impairment, inflammatory phenotype, comorbidity scores, and molecular features. However, we found that WM patients with at least an abnormal clone were older at diagnosis (median age 72 years vs 65 years, p = 0.003). (Table 1)

Moreover, advanced age was also found to correlate with the number of abnormalities since WM patients with CK had a median age significantly higher than that of the subject with 2 or less cytogenetic aberrations (85 vs 66 years, respectively, p < 0.001). Similarly, patients with 2 or more cytogenetic aberrations were older than patients with 0 or 1 alterations (median age 80 vs 66 years, respectively, p < 0.001). (Table 3).

Among patients with a normal karyotype, 26 out of 34 (76%) required treatment whereas among those with an altered karyotype 18 out of 30 (60%) needed therapy. The criteria for initiating first-line therapy were evenly distributed between the two groups. Anemia, hyperviscosity, and neuropathy were the most prevalent causes in our population (Table 1).

The number of subsequent lines of therapy administered after the first one was also similar between the two groups. Conventional chemoimmunotherapy was the most frequent type of treatment administered. Bruton Tyrosine Kinase (BTK) inhibitors were used at similar frequencies in the two groups and major response after the first line of therapy was achieved in 4 out of 5 cases.

Major response rate to first line therapy tended to be higher in the normal karyotype subgroup although statistical significance was not reached (62% vs 39%, p = 0.13). No substantial differences were seen in disease progression rate after first line therapy (20% vs 23.5%) during the entire follow up period. The percentage of death events was superior in patients with abnormal cytogenetics when compared to those with a normal karyotype (8/30 [27%] and 4/34 [12%], respectively). Of the patients for whom the cause of death was well-established two died due to secondary cancers in abnormal karyotype subgroup, while in the other subgroup three patients died due to sepsis and one due to lymphoma transformation.

Table 2

Summary of cytogenetic analysis
Cytogenetic feature	Frequency (%)
Karyotype
Abnormal	30/64 (46.9%)
Normal	34/60 (56.6%)
Number of aberrations in the karyotype
1	17/30 (56.6%)
2	7/30 (23.3%)
≥ 3 (complex and high-complex)	6/30 (20.0%)
Type of aberrations in the karyotype
Numerical only	11/30 (36.6%)
Structural only	13/30 (43.3%)
Numerical and structural	6/30 (20.0%)
Recurrent aberrations in the karyotype (in more than 3 cases)
Deletion 6q	7/30 (23.3%)
Trisomy 3/partial + 3	7/30 (23.3%)
Deletion 11q	4/30 (13.3%)
Trisomy 12/partial + 12	4/30 (13.3%)
Trisomy 18	4/30 (13.3%)
Loss of Y	4/30 (13.3%)

Table 3

**Median age at diagnosis according to the karyotype**
Subgroups	Median age at diagnosis, years (IQR)	P value
Abnormal karyotype	72 (66–82)	0.003
Normal karyotype	65 (58–70)	0.003
≥ 2 cytogenetic aberrations	80 (72–84)	< 0.001
< 2 cytogenetic aberrations	66 (59–72)	< 0.001
Complex karyotype	85 (83–87)	< 0.001
No complex karyotype	66 (59–73)	< 0.001
IQR = interquartile range

When performing survival analyses, we found that WM patients with cytogenetic aberrations displayed inferior median overall survival (mOS) compared to those with a normal karyotype (76.1 vs 167.7 months, respectively [p value = 0.01]) and similar trend were noted for the median progression free survival (mPFS) in the two subgroups with (65.8 vs 117.8 months, respectively [p value = 0.01]). (Fig. 1A and 1B). Furthermore, the PFS curves diverged even more after 40 months. Additionally, no clinical and biochemical features related to WM disease were distributed differently between the groups beyond this time point.

WM patients with ≥ 2 chromosome changes exhibited an inferior mOS compared to those with 1 or 0 abnormalities (52.3 vs 167.7 months, respectively [p value = 0.02]) and a trend towards an inferior mPFS was also observed (52.3 vs 108.9 months, respectively [p value = 0.06]). The same held true for cases with or without CK. In fact, the CK subgroup exhibited significantly shorter mOS (52.3 vs 167.7 months respectively [p value = 0.004]) and mPFS (38.6 vs 108.9 months, respectively [p value < 0.001]). (Table 4).

As mentioned above, the described difference in terms of survival outcomes was maintained even with the increase of the number of aberrations (Fig. 1C, 1D, 1E, 1F). A univariate Cox proportional hazard regression analysis was conducted, examining various features. None of the considered variables (disease burden, renal impairment, inflammatory phenotype, comorbidity scores, and molecular features) were found to have a significant correlation with the observed differences in survival outcomes, thus suggesting an independent role of cytogenetic abnormalities in determining inferior outcomes in WM patients.

Table 4

Overall and progression free survival outcomes according to the karyotype
Subgroups	Median OS (months)	HR (CI 95%)	P value	Median PFS (months)	HR (CI 95%)	P value
Normal karyotype	76.1	4.35 (1.27–14.86)	0.01	65.8	2.90 (1.24–6.83)	0.01
Abnormal karyotype	167.7	4.35 (1.27–14.86)	0.01	117.8	2.90 (1.24–6.83)	0.01
≥ 2 cytogenetic aberrations	52.3	5.28 (1.15–24.31)	0.02	52.3	2.69 (0.92–7.81)	0.06
< 2 cytogenetic aberrations	167.7	5.28 (1.15–24.31)	0.02	108.9	2.69 (0.92–7.81)	0.06
Complex karyotype	52.3	9.14 (1.56–26.11)	0.004	38.6	6.05 (1.85–19.79)	< 0.001
No complex karyotype	167.7	9.14 (1.56–26.11)	0.004	108.9	6.05 (1.85–19.79)	< 0.001

HR = Hazard Ratio; CI 95% = 95% confidence interval; OS = Overall Survival; PFS = Progression Free Survival

In the present study, we have analyzed the features and the outcomes of a cohort of WM patients from an academic institution, dividing the included subjects based on the presence and the number of chromosomal abnormalities detected at diagnosis.

In line with the above mentioned French study, we detected a similar prevalence of the deletion of 6q (23.3%).¹⁰ However, our findings also revealed a high frequency of trisomy of the chromosome 3 (23.3%) which was among the less reported alterations in the French investigation. Higher frequency of Y loss (13.3%) and 11q deletion (13.3%) were also detected. Notably, trisomy of chromosome 4 did not emerge as a recurrent alteration in our case series.¹⁰ The search for chromosome 17 deletion has been performed in a minority of cases and for this reason this alteration could not be compared to previously published data. The prevalence of complex karyotype showed similar frequency (13.3%) to that described in the FILO study even if we reported a lower number of patients with High-CK.¹⁰ With the exception of 6q-, which is typical of WM, all the reported alterations are recurrent in low-grade B-cell lymphoproliferative disorders, and the varying frequency of each is likely dependent on the size of the studied sample and the stage of the disease under investigation.

None of previously published studies have investigated the potential association between age and cytogenetic abnormalities. Indeed, our analysis suggests a correlation between older age and a higher prevalence of cytogenetic aberrations. This association appeared to be stronger when comparing patients with CK to patients without CK, confirming our recently published findings in a study involving very elderly WM patients.⁷ A longstanding condition of monoclonal gammopathy preceding the diagnosis of Waldenström Macroglobulinemia and the treatment could probably influence karyotype characteristics determining inferior survival outcomes. Older age could also be responsible for the observed higher rate of secondary malignancies in the aberrant cytogenetic subgroup. However, neither second tumors nor lymphoma were prevalent causes of death in our series.

Unlike the aforementioned studies, we did not find a positive correlation between disease burden or inflammatory WM and cytogenetic abnormalities. Nonetheless, elevated IPSSWM scores was found in the abnormal karyotype subgroup, but this is possibly attributable to a major prevalence of older patients. When evaluating the single cytogenetic aberrations (either structural or numeric) we did not find an impact on survival outcomes. These results, however, could be biased by the small numerosity of the cohort. In all the comparisons among subgroups (normal versus abnormal karyotype, ≥ 2 versus < 2 cytogenetic aberrations, CK versus normal karyotype) the independence of cytogenetics from clinical or biological variables was maintained, with the significant exception for age atdiagnosis.

On the other hand, in comparing the subset of patients with altered karyotype to those without chromosome changes, we found a trend towards a correlation between inferior OS and PFS and the increase of the number of cytogenetic aberrations. (Fig. 1). Within the first 40 months following diagnosis, patients with an altered karyotype exhibited a comparable rate of relapse events to those with a normal karyotype. Beyond this time point, the frequency of relapse events substantially increased for the individuals with altered cytogenetics. While the cause of this late divergence requires further investigation, it is conceivable that the presence of chromosomal abnormalities may confer increased inherent resistance to subsequent line of therapies thereby leading to more relapses or death events. Additionally, no clinical and biochemical difference were noticed between groups beyond this time point.

Differently from what we have reported here, a recent Chinese study did not find statistically significant survival differences in WM patients with two or more cytogenetic aberrations compared to patients with a single alteration or a normal karyotype.^15,16 However, in line with previously published data, we found no substantial differences in terms of response to therapy, nor we found any specific relationship between cytogenetics and the type of therapy administered.¹⁰ Moreover, even if with the limit of a small numerosity, it seems that the use of BTKi might be associated with better response rates when employed in elderly patients with altered karyotype, a finding that should deserve further investigation. Furthermore, we have not found specific causes determining the inferior OS in the aberrant cytogenetic subgroups as the spectrum of causes of death in our patients was heterogeneous.

Our cohort demonstrated to be comparable to larger retrospective studies such as the French one in terms of karyotype alterations, with the exception for the absence of consistent TP53 mut/del. While our study is limited by the small numerosity and the retrospective design, it has the advantage that cytogenetic analysis was handled by a single laboratory.

In conclusion, our data contributes to suggest an independent role of the karyotype on survival outcomes in WM patients. The impact on outcomes seems to be proportional to the number of abnormalities, being increasingly worst for patients with one, two, three or more cytogenetic aberrations. With the exception for older age at diagnosis, no positive correlation between altered karyotype and disease burden, MYD88/CXCR4 mutation or inflammatory WM has been found. The positive correlation between age and the number of cytogenetic aberrations could at least in part be related to a different biological background in this group of patients. Our study also underlines the importance of karyotype testing, along with the mutational screening, at diagnosis in WM, to obtain better outcome predictions in subjects affected by this rare malignancy.

Author contributions: ND, LT and FP conceived the study, collected and analyzed the data and wrote the manuscript. LB, AM, SN, RB, SC, RM, SM performed karyotyping and molecular studies and analyzed the data. FS, MP, APDT performed the pathological analysis. AC, GS and AV collected and analyzed the data.

Disclosures: The authors have no competing interests to declare that are relevant to the content of this article.

Ethical approval: Data have been collected according to the protocol (4089/AO/17) approved by the Ethic Committee of the Azienda Ospedale-Università di Padova. A written consent was obtained by the patients.

Data availability declaration: The data that support the findings of this study are available upon request from the corresponding author.

Funding declaration: No funding was received to assist with the preparation of this manuscript.

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No competing interests reported.

Impact of the presence and number of chromosomal abnormalities on the clinical outcome in Waldenström Macroglobulinemia: a monocentric experience

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Abstract

Figures

Introduction

Material and methods

Statistical analysis

Chromosome banding and molecular analyses

Results

Discussion

Declarations

References

Additional Declarations

Status:

Journal Publication

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