International Journal of Hematology and Therapy | Volume 5 | Issue 1 | 2019-03-12

Cladribine in the Treatment of Waldenstrom Macroglobulinemia, where do we stand?

Marlies Van Hoef

Abstract

Waldenstr m macroglobulemia is a rare disease for which treatment with cladribine (2-chorodeoxyadenosine) has been reported since 1993. Cladribine has meanwhile been administered to several hundreds of reported patients either as monotherapy or in combination therapy and is available for intravenous and subcutaneous administration. Cladribine has been used in treatment naive and previously pretreated patients. Literature describing the use of cladribine, combinations of other medications and ibrutinib in Waldenstrom s Macroglobulinemia is reviewed herein.

Keywords: Waldenstrom macroglobulinemia, Cladribine, Combination treatment, Ibrutinib review

Full text

Waldenstr m Macroglobulinemia (WM) is a rare indolent B-cell lymphoproliferative disorder characterized by the accumulation of monoclonal cells in the bone marrow and peripheral lymphoid tissues, and associated with the production of serum immunoglobulin M (IgM) monoclonal protein. The age-adjusted annual incidence rate is 3.4 per million in men and 1.7 per million in women in the United States and 7.3 and 4.2 per million respectively in Europe [1,2] . The disease accounts for approximately 1% to 2% of non-Hodgkin lymphomas. The main clinical symptoms arecytopenia, hyperviscosity syndrome, epistaxis, constitutional symptoms, lymphadenopathy and hepatosplenomegali. The diagnosis is confirmed by the presence of IgM monoclonal protein in the serum and a bone marrow biopsy showing > 10% clonal lymphoplasmacytic cells. Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog that was developed in the 1970s. It was first tested in humans in the early 1980s. Cladribine is a chemotherapeutic compound that can be administered intravenously or subcutaneously. It is a prodrug that is activated after uptake in cells [3] . It functions as an antimetabolite and is toxic in hematopoietic cells and leukemic and lymphatic malignancies, but has little or no effect in non-hematopoietic tissues and solid tumors. It is polyvalent and is toxic for dividing and quiescent cells [3] . Cladribine induces myelosuppression and immunosuppression. A review of its efficacy in WM is described in this paper. Review Table 1 displays studies with cladribine for symptomatic WM that have been reported chronologically over time. Table 1 : Cladribine in patients with WM Author Pretreatment Treatment Patients ORR PFS OS Commend 4)Dimopoulos MA Pretreated 20 Untreated 9 Cladribineiv 2 cycles 29, median age 65y ORR 17 (59%) 100% untreated 40% pretreated At 7m follow-up 1 responding pat had relapsed At 7m OS 89.7% 5)Dimopoulos MA Pretreated 53 Untreated 15 Fludarabine (28) Cladribine iv (40) median 5 cycles 68 ORR 35 (51.5%) 4 CR ORR cladribine untreated 92% pretreated 48% At 18m follow-up in untreated pat 86.7%. Med DOR in pretreated pat 38m. At 18m OS in untreated pat 100%. Med OS in pretreated pat 43m. At analysis 2 of 15 untreated patients had relapsed 6)Zaucha JM Untreated 1 Cladribine iv 1, aged 68y ORR 1 (100%) 1 PR 7) Dimopoulos MA Pretreated Fludarabine 14 Cladribine iv 2 cycles 14 ORR 4 (28.6%) 4 PR 8) Delannoy A Pretreated 13 Untreated 5 Cladribine iv median 2 cycles 18, median age 69y ORR 7 (38.8%) 7 PR 9) Dimopoulos MA Untreated 26 Cladribine iv 2 cycles 26 ORR 22 (85%) 3 CR, 19 PR At 13m follow-up 5 pat had relapsed At 13m OS 81% Pat retreated after relapse had again response 10) Dimopoulos MA Pretreated 46 Cladribine iv 2 cycles 46 ORR 20 (43%) Median 12 months Median 28 months Response dependendent on disease state 11)Richards AI, J Untreated 1 Cladribine iv 4 cycles 1, meningeal involvement 1 CR (100%) DFS 15+ m 12) Fridrik MA Untreated 10 Cladribine iv 4 cycles 10, median age 62.3y ORR 100%, 1 CR, 8 PR, 1 MR At median 57w 70% At median 57w 90% 13) Betticher DC Pretreated except for 1 pat Cladribinesc max 6 cycles 25, median age 65y ORR 68% incl. dis. Stabilization 10 PR (40%) Med DOR 8m 14)Liu ES Untreated 7 Pretreated 18 Cladribine iv 3 cycles with continuation if PR achieved 20, median age 66y ORR 55%, 1 CR, 10 PR At 20m 85% 57% untreated and 54% pretreated responded 15)Hellmann A Untreated 9 Pretreated 13 Cladribine iv 4 cycles 22, median age 62y ORR 41% 1 CR, 8 PR, 10 stabilization Mean DOR in responders 12m Response 38% in pretreated, 44% in untreated 16)Lewandowski Untreated 11 Pretreated 14 Cladribine iv, mean 3 cycles 25, mean age 63y ORR 64% 1 CR, 15 PR Six patients obtained stable disease 17)Weber DM Untreated 94 Cladribine iv vs Clad iv + Pred vs Clad sc + Cyclo vs Clad sc + CycloRitux 2 cycles 16, med age 67y 20, med age 61y 17, med age 62y 9, med age 63y ORR 94%, 3 CR ORR 60%, 1 CR ORR 84%, 2 CR ORR 94%, 3, CR Med DOR 23 m Med DOR 9 m Med DOR 36 m DOR NR at med 21m Median 73 m Median 41 m Not reached Not reached 2 nd line ORR 80% 2 nd line ORR 88% 2 nd line ORR 77% 18)Laszlo D Untreated 16 Pretreated 13 Cladribinesc + Rituximab 4 cycles 29, median age 64y ORR 89.6%, 7CR, 16 PR, 3 MR At 43m FU 4 patients relapsed No difference in response pretreated and untreated ORR=overall response rate, PFS=progression free survival, DFS=disease free survival, OS=overall survival, CR=complete response, PR=partial response, MR=minor response, DOR=duration of response, iv=intravenous, sc=subcutaneous, Clad= cladribine, Pred= prednisone, Cyclo= cyclophosphamide, CycloRitux= cyclophosphamide, rituximab, m=months, FU=follow-up In the initial reports cladribine was administered as monotherapy for two to five cycles intravenously and up to six cycles subcutaneously [4-16] . In studies at later date cladribine was administered in combination treatment [17,18] . Cladribine two to four cycles induced overall response rates from 85% to 100% in treatment na ve patients [4-17] . Among responders were complete response [9-18] . Overall response rates were lower in studies that combined treatment naive and pretreated patients and varied from 28.6% to 89.6% [4-18] . The variation may depend on number of prior treatments and the percentage of untreated patients in the cohort. Dimopoulos et al. found an overall response rate of 92% to 100% in untreated and 40% to 48% in pretreated patients with two cycles of cladribine [4,5] . In a study reporting cladribine, with cladribine plus prednisone, cladribine plus cyclophosphamide, or cladribine plus cyclophosphamide plus rituximab in treatment na ve patients, response rates with two cycles of cladribine monotherapy (94%) were comparable with those with the two latter combinations (84% and 94%) respectively and higher than those when cladribine was combined with prednisone (60%) [17] . In this study retreatment with cladribine in second line resulted in response rates of 77% to 88%. Successful retreatment after relapse had already previously been reported [9] . Duration of response and progression free survival was longer for treatment naive than for pretreated patients. In treatment na ve patients response duration was in general longer when cladribine was used in combination than when cladribine was used as monotherapy, but the number of cycles administered may also have influenced the response duration . Weber et al. reported median response durations of 23 months, 9 months, 36 months and not reached at median 21 months with respectively cladribine, cladribine plus prednisone, cladribine plus cyclophosphamide and cladribine plus cyclophosphamide plus rituximab in treatment na ve patients who received two cycles [17] . Ten of fifteen patients responding to cladribine, eight of twelve responding to cladribine and prednisone, and thirteen of thirty one responding to cladribine plus cyclophosphamide were retreated with the same therapy after relapse [17] . The duration of second remission was similar to the first remission, being 24, 14 and 30 months respectively. Laszlo et al. reported a response rate of 79.7% in treatment na ve and pretreated patients who received subcutaneous cladribine and rituximab [18] . At 43 months follow-up relapse free survival was 84.6 % in patients who had responded to four cycles of the combination of cladribine and rituximab. Durations of response or progression free survival in studies with cladribine monotherapy including treatment na ve and pretreated patients were shorter than in studies including treatment na ve patients only, Cladribine was in general administered intravenously but subcutaneous administration was also reported . In the various studies cladribine intravenously was given at a dose of 0.1 mg/kg/d continuously for 7 days or at a dose of 0.12 to 0.14 mg / kg / d or 4 to 5.6 mg/m2/d over two hours for five days. Subcutaneous injection occurred at a dose of 0.1 mg / kg / d for five days either as monotherapy or in combination therapy. Subcutaneous and intravenous administration are equally efficient but subcutaneous administration is more convenient and cost-saving [19,20] . Various treatments for WM other than cladribine have been reported in studies that included patients with treatment na ve symptomatic WM: Table 2 displays regimens that have been reported in treatment na ve patients. Dexamethasone plus rituximab plus cyclophosphamide induced overall response rates of 83% to 96% in treatment na ve patients [21-23] . Median progression free survival exceeded two years and was 34 to 35 months [21-23] . Castillo et al. reported three different combination treatments including rituximab and rituximab maintenance and observed a major response rate of 97% in treatment na ve patients compared to 68% in patients who received no maintenance [24] . Progression free survival was median 6.8 years with and 2.8 years without rituximab maintenance and overall survival 84% with and 66% without rituximab maintenance [24] . Half-dose cyclophosphamide, doxorubine, vincristine, prednisone plus rituximab (CHOP-R) induced an overall response of 65% and a progression free survival at two years of 70% in treatment na ve patients [25] . Three bortezomib plus rituximab containing treatment regimens induced overall response rates of 85% to 96% in treatment na ve patients [26-28] . This combination resulted in an event free survival of 79% at one year [28] ; when dexamethasone was added median progression free survival was 42 months and with rituximab maintenance progression free survival at 22.8 months was 78.3 % (26,28). Carfilzomib, rituximab plus dexamethasone with same maintenance regimen resulted in 87.1% overall response rate, and at 15.4 months progression free survival in 64.5% of patients naive to bortezomib and rituximab [29] . Ibrutinib induced 100 % overall response in 30 treatment na ve patients [30] . At 14.6 months follow-up 6.7 % of patients had relapsed. The effect of continuous (maintenance) treatment with ibrutinib became apparent in a study reported by Gustine at al., who reported an IgM rebound 4 weeks after discontinuation of ibrutinib [31] . Table 2 : Studies with other medications that included treatment naive WM patients Author Pretreatment Treatment Patients ORR PFS/DFS OS Commend 21. Dimopoulos MA untreated DexaRituxCyclo 8 cycles 72 ORR 83% 7% CR, 67% PR, 9% MR 2y PFS 67% and for responders 80% 2y OS 90% Median time to response 4.1m 22.Kastritis E untreated DexaRituxCyclo at 7y FU, retreatment upon relapse 72 ORR 83% 7% CR, 67% PR, 9% MR Med PFS 35m 8y OS 64% 10y estimated OS 53% Med PFS rituxalone 23m, rituxcombination 3y 23.Paludo J 50 untreated 50 rel /ref DexaRituxCyclo 100 ORR 87% Untreated ORR 96% Med PFS 32m Untreated med PFS 34m Med TTNT 50m Untreated med TTNT NR 24.Castillo JJ Untreated DexaRituxCyclo DexaBortezoRituxBendaRitux maintenance Ritux vs no maintenance 38 87 57 116 Med TTBR 30m Med TTBR 20m Med TTBR 18m Major R 97% vs 68% Med PFS 4.8y Med PFS 5.8y Med PFS 5.5y Med PFS 6.8y vs 2.8y 10y OS 81% 10y OS 96% 10y OS 95% 10y OS 84% vs 66% Maintenance added ORR, PFS and OS 25.Sekiguchi N Untreated ½ dose CHOP-R 6 cycles 20 ORR 13 (65%) 2y PFS 70% 2y OS 93.3% 26.Treon SP Untreated DexaBortezoRitux 4 cycles induction, 4 cycles mainten 23 ORR 96%, Major R 83%, 3 CR At 22.8m PFS 78.3% Responses after 1.4 months 27.Ghobrial IM Untreated BortezoRitux 4 cycles, Ritux in cycles 1 and 4 26 ORR 88% 1CR, 1 nCR , 15 PR, 6 MR 1y EFS 79% 28.Dimopoulos MA Untreated DexaBortezoRitux 5 cycles, with DexaRitux in c 2+5 59 ORR 85%, 3% CR, 7% VGPR 58% PR Med PFS 42m 3y DOR 70% 3y OS 81% Peripheral neuropathy in 46% 29.Treon SP Na ve to Bortezo + Ritux CarfilzoRituxDexa Maintenance same mainten 8 cycles 31 ORR 87.1% 1 CR, 10 VGPR, 10 PR, 6 MR At 15.4m 20 pat progression free 30.Treon SP Untreated Ibrutinib 30 ORR 100%, Major R 83% At 14.6 m FU, 2 pat progressed Estimated 18m PFS 92% Wild type CXCR4 vs CXCR4 major r 94% vs 71%, VGPR 31% vs 7% 31.Gustine JN Discontinuation of ibrutinib Ibrutinib 189 51 discontinue IgM rebound 4 wk after discon in 73%; ORR to salvage 71% OS shorter if progressive on ibrutinib Discontinuation at 12,24,36,48m 22%, 26%, 35%, 43% ORR=overall response, PFS=progression free survival, DFS=disease free survival, EFS=event free survival, OS=overall survival, CR=complete response, nCR=near complete response, VGPR=very good partial response, PR=partial response, MR=minor response, major r=major response, DOR=duration of response, TTBR=time to best response, med=median, m=months, y=year, TTNT=time to new treatment, NR=not reached, FU=follow=up, rel/ref=relapsed/refractory, DexaRituxCyclo= dexamethasone, rituximab, cyclophosphamide, DexaBortezoRitux= dexamethasone, bortezomib, rituximab, BendaRitux= bendamustin, rituximab, CHOP-R= cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab, CarfilzoRitux,Dexa =carfilzomib, rituximab, dexamethason Various treatments for WM other than cladribine have been reported in studies that included symptomatic treatment na ve and relapsed and / or refractory patients: Table 3 displays regimens that have been reported in such studies. Cyclophosphamide and fludarabine for four cycles induced overall response rates of 55% to 76% with a median progression free survival of 24 months and median duration of response of 38 months in treatment na ve and pretreated patients [32,33] . The overall response rate with four fludarabine based combinations was 90% and median progression free survival 43.1 months [34] . Fludarabine, cyclophosphamide plus rituximab for at least four cycles induced an overall response of 79% to 85.4% and at median 47 to 51 months median progression free survival was not reached [35-37] . In one report median event free survival was 77 months [36] . Pentostatin combined with cyclophosphamide with or without rituximab induced an overall response of 64.7% and maintenance rituximab prevented relapse in 58.8% of treatment na ve and pretreated patients [38] . The same regimen induced two years progression free survival in 83.7% and when this regimen was in addition used as maintenance the progression free survival increased to 91.7% [39] . Bendamustine plus rituximab induced response rates from 80.2% to 95% in pretreated patients [40-42] . Median progression free survival varied from 13.2 months to 58 months [40-42] . Dexamethasone, rituximab plus cyclophosphamide induced an overall response of 87% in treatment na ve and pretreated patients [24,43] . Median progression free survival was 32 months [23,42] . Cyclophamide, doxorubicine, vincristine, prednisone plus rituximab with rituximab maintenance in part of the patients induced a high overall response of 92.3% in treatment na ve and relapsed and refractory patients and at 9 months a progression free survival of 76.9% [43] . Two bortezomib plus rituximab based combination treatments induced an overall response of 81% and 89% in pretreated patients [44,45] . The median time to progression and was 15.6 months and the median progression free survival 21 months respectively [44,45] . Bortezomib monotherapy or bortezomib plus prednisone though induced lower response of 43.2% in advanced WM [46] . Dimopoulos et al. reported an overall response of 90%, with 71% major response with ibrutinib in rituximab refractory patients, who had received median four prior cycles [47] . Median progression free survival at 18 months was 86%. In another study including treatment na ve and pretreated patients ibrutinib plus rituximab induced an overall response of 92% with 72% major response [48] . Ibrutinib was administered continuously and at 30 months progression free survival was 82% [48] . Table 3: Studies with other medications that included treatment naive and pretreated patients with WM Author Pretreatment Treatment Patients ORR PFS/DFS OS Commend 32. Dimopoulos MA 7 refractory 2 relapsed 2 untreated FludaC yclo 4 cycles 11, median age 73y PR 6 (55%) Med PFS 24m At 28m FU, 2 of 6 responders progressed 33.Tam CS 4 untreated 14 pretreated FludaCyclo 4 cycles 18 PR 13 (76%) Med DOR 38m At 37m for untreated pat 100% 5y OS pretrea -ted pat 55% 34.Peinert S 10 untreated 19 pretreated FludaCyclo FludaCycloRitux FludaMitox FludaRitux 29 ORR 26 (90%) 1 CR, 23 PR, 2 MR Med PFS 43.1m 5y OS 88% 10y OS 75% Untreated patients all responded and alive at med 50m 35.Tedeschi A Untreated Pretreated FludaCyclo Ritux 6 cycles 43 ORR 79% Major response 74.4% After FU continuation improvement leading to 18.6% CR 36.Tedeschi A Untreated Pretreated FludaCycloRitux 40 ORR 32 (80%) VGPR 32.5% Med EFS 77m At med 51m FU, med PFS NR 37.Souchet L 25 untreated 57 pretreated FludaCycloRitux 5 cycles 82, MED AGE 61y ORR 85.4% At med FU 47m, med PFS NR 48m PFS 67% 3y OS 90% Best response at 10.8 months major resp from 64.6% to 76.8% 38.Hensel M 9 untreated 8 pretreated PentostCyclo + Ritux + maintenance ritux 4-6 cycles 17 ORR 11 (64.7%) 2 CR, 9 PR Maintenance rituximab prevented relapse in 10 pat In pat who received rituximab ORR 76.9% 39.Herth 21 untreated 4 pretreated PentostCycloRitux 25 1 st line 2y PFS 83.6%, same for maintenance 91.7% 1 st line 2y OS 100%. Same for maintenance 100% 13 pat had rituximab maintenance 40.Treon SP Rel /ref BendaRitux Benda + ofatum 5 cycles 30 ORR 25 (83.3%) 5 VGPR, 20 PR Med PFS 13.2m 41.Tedeschi A Rel /ref Median 2 lines of treatment BendaRitux 71, med age 72y ORR 80.2% Major response 74.6% At med 19 m med PFS NR 42.Paludo J 43 rel /ref 50 rel /ref BendaRitux DexaRituxCyclo 60 100 Na ve ORR 93% vs 96% Rel /ref ORR 95% vs 87% Na ve 2y PFS 88% vs 61% Rel /ref med PFS 58 vs 32m Med OS NR vs 166m 23.Paludo J 50 untreated 50 rel /ref DexaRituxCyclo 100 ORR 87% Untreated ORR 96% Med PFS 32m Untreated med PFS 34m Med TTNT 50m Untreated med TTNT NR 43.Treon SP 3 untreated 3 rel / 7 ref CHOP-R 6 cycles 3 pat maintenance Ritux 13 ORR 12 (92.3%) 3 CR, 8 PR, 1 MR At 9 m PFS 10 of 13 (76.9%) 44.Ghobrial IM Pretreated at least one prior therapy BortezoRitux 4 cycles, Ritux in cycles 1 and 4 37 ORR 81% 2 CR, 17 PR, 11 MR Med time to progression 15.6m 12m PFS 57% 18m PFS 45% 45.Ghobrial IM Rel /ref EverolRitux EverolBortezoRitux maintenanceEverol 6 cycles 10 36 ORR in 36 89% 2CR, > PR 19 (53%) Med PFS 21m 46.Leblond V Advanced WM Bortezo ; in nonres-ponding patients dexa after 2 nd cycle 6 cycles 34 ORR after 2 cycles 43.2% Med PFS 15.3m 47. Dimopoulos MA Ritux refractory Median 4 prior therapies Ibrutinib 31, medianage 67y At med 18.1m ORR 90%, 71% major resp 18m PFS 86% 18m OS 97% Time to 1 st response 1m 48.Dimopoulos MA Untreated 45% Pretreated 55% IbrutinibRitux vs PlaceboRitux 150 ORR 92% vs 47% major response 72% vs 32% VGPR 23% vs 4% At 30m PFS 82% vs 28% At 30m OS 94% vs 92% At 24m in pat with major resp DOR 92% vs 41% ORR=overall response, PFS=progression free survival, DFS=disease free survival, OS=overall survival, CR=complete response, VGPR=very good partial response, PR=partial response, MR=minor response, DOR=duration of response, NR=not reached, TTNT=time to next treatment, FU=follow-up, rel/ref=relapsed/ refractory, FludaCyclo= fludarabine, cyclophosphamide, FludaCycloRitux= fludarabine, cyclophosposphamide, rituximab, FludaMitox= fludarabine, mitoxantrone, PentostClyco= pentostatin, cyclophosphamide, BendaRitux= bendamustine, rituximab, DexaRituxCyclo= dexamethasone, rituximab, cyclophosphamide, CHOP-R= cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab, BortezoRitux= bortezomib, rituximab, EverolRitux= everolimus, rituximab Discussion Comparing the response rates of two to four cycles cladribine monotherapy subcutaneous or intravenous in treatment na ve patients (85% to 100%) with those of other combination regimens of which at least four cycles were administered (dexamethasone, rituximab, cyclophosphamide 83% to 96% [21,23] triple combinations with or without rituximab maintenance 97% vs 68% [24] , cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab 65% [25] , dexamethasone, bortezomib, rituximab with or without maintenance 96% vs. 85% [26,28] , dexamethasone, bortezomib, rituximab 85% to 88% [27,28] , dexamethasone, carfilzomib, rituximab with maintenance 87.1% [29] and ibrutinib 100% [30] ), cladribine monotherapy induced high response rates and good durations of response. Compared to ibrutinib, it needs to be considered that ibrutinib has to be taken continuously, and that an IgM rebound occurs after discontinuation whereas only two to four cycles of cladribine are required to induce 85% to 100% overall response for a median duration of 23 months in treatment na ve patients . Thus cladribine, which can be administered subcutaneously, is a cost-saving treatment in situations in which ibrutinib is not available, or costs of ibrutinib treatment prevent the use, Cladribine monotherapy was moderately efficient in studies in which treatment na ve and pretreated patients were combined (28.6% to 68%). However, the combination of subcutaneous cladribine plus rituximab for four cycles induced an overall response of 89.6 % in treatment na ve and pretreated patients, and at 43 months follow-up only four of twenty six patients had relapsed for a relapse free survival of 84.6% [18] . With other combinations in studies in which treatment na ve and pretreated patients were combined response rates were as following: fludarabine, cyclophosphamide 55% to 76% [32,33] , fludrabine, cyclophosphamide, rituximab 79% to 90% [34-37] pentostatine, cyclophosphamide with or without rituximab 64.7% [38] , bendamustine, rituximab with or without cyclophosphamide 87% vs. 80.2% [23,40-42] , cyclophosphamide, doxorubine, vincristine, prednisone, rituximab and rituximab maintenance 92.3% [43] , bortezomib combinations 81% to 89% [44] , bortezomib monotherapy 43.2% [46] , ibrutibinib 90% [47] and ibrutinib,rituximab 92% [48] . Thus the cladribine with rituximab combination induced overall response rates that were comparable with other combinations [18] . Also in this setting cladribine with rituximab would be a good alternative in case ibrutinib is not available or costs of ibrutrinib treatment prevent the use. 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