|Year : 2022 | Volume
| Issue : 1 | Page : 58-62
CLL management in 2022: Indian settings
Narendra Agarwal, Megha Verma
Department of Hematology and Bone Marrow Transplant, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
|Date of Submission||06-Jun-2022|
|Date of Decision||20-Jun-2022|
|Date of Acceptance||27-Jun-2022|
|Date of Web Publication||02-Sep-2022|
Dr. Narendra Agarwal
Department of Hematology and Bone Marrow Transplant, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, Delhi 110085
Source of Support: None, Conflict of Interest: None
Chronic lymphocytic leukemia (CLL) is being increasingly recognised in our adult population. Though typically a disease of elderly, many young patients are also being diagnosed especially in Indian subcontinent. It shows a heterogenous clinical course. The diagnosis is established by complete blood counts, blood smears morphology, and immunophenotyping. The diagnosis is made with identification of clonal B-cell population. The clinical staging systems includes results of physical examination and peripheral blood counts. In addition, there are various biological and genetic markers for further prognostic information. The clinical staging and genetic findings guide us for assessing the need to treat and for selection of therapies. The CLL international prognostic index combines the genetic, biological, and clinical variables for risk stratification of patients with CLL. Only selected patients warrant therapy at the time of diagnosis. In the current settings with availability of newer targeted therapies and chemotherapy, clinicians and patients can together choose amongst the available therapeutic regimens. The targeted therapy includes the Bruton kinase inhibitors including Ibrutinib, acalabrutinib and Bcl2 directed therapy with Venetoclax. These therapies can be used as single agent therapy or in combination. Though in west, therapy has majorly shifted to targeted therapy from chemotherapy, we in India are still in the transition phase. Future challenges: Potentially curative treatment regimen of finite duration is being investigated. More studies are needed for improving the outcomes of poor risk group with del17p, Tp53 deletion and in refractory cases. The optimal sequencing of targeted therapies also needs to be determined.
Keywords: CLL, hematology, lymphoma
|How to cite this article:|
Agarwal N, Verma M. CLL management in 2022: Indian settings. J Curr Oncol 2022;5:58-62
| Introduction|| |
The growing knowledge of disease biology of chronic lymphocytic leukemia(CLL) has translated into major breakthrough in management of disease. The patients are now enjoying better quality of life with increased overall survival. Two group of agents, the Bruton tyrosine kinase inhibitors(BTKis) and the B cell lymphoma 2 group of protein(BCL2) targeted therapy are the recent FDA approved molecules and they form the cornerstones of this paradigm shift in CLL therapy. These new molecules have their unique toxicity profiles, ibrutinib the first widely used BTKi is associated with cardiac toxicities, bleeding risk. This led to development of specific BTKi Acalabrutinib, with a more favorable toxicity profile. Venetoclax, a BCL2 target therapy offers a finite duration therapy and has been FDA approved for CLL in 2016. It is associate with high risk of tumor lysis and needs proper dosing schedule. With the availability of these drugs questions of which group of agents to be used first remains unanswered, randomized trials comparing these new molecules head to head are required. Despite this advancement there are few groups with TP53 mutation/17p deletion which continue to perform poorly and need further study.
The western medicine has quickly adopted these agents as first line and they are preferred over chemotherapy. Now with development of generic molecules and easier availability of these newer agents, we in India are also slowly moving toward the chemotherapy free approach. Here in this review we discuss the tremendous success attained in CLL therapy over the past few years, and how these new therapies are being incorporated in Indian settings and role of chemotherapy in current times.
Diagnosis and management of naïve CLL in Indian settings
The incidence of Chronic lymphocytic leukemia(CLL) shows demographic variation, it is reported as the most common in the United States Of America (>30%) while is the least common leukemia reported in India(<5%). According to SEER data the median age at diagnosis is 70 years with only 9.1% of patients with CLL younger than 45 years. Studies have shown younger age of presentation in Asians with a median age of 61 years.
There are data to suggest that the clinical presentation of CLL in the Asian population may be different. This is observed with younger age of diagnosis and a shorter time to treatment initiation. Indian studies reported a high proportion of CLL patients presenting with advanced clinical stage with higher mortality., So, ethnicity may have a major impact on the prevalence of chronic lymphocytic leukemia (CLL) and also influence disease phenotype. More population-based studies are required to prove the difference.
The diagnosis of CLL is made with the presence of ≥5 × 109/L B lymphocytes in the peripheral blood, sustained for at least 3 months. these lymphocytes are morphologically characterized by a small mature look with condensed chromatin and the presence of smudge cells. The clonality of lymphocytes is demonstrated by peripheral blood immunophenotyping).,
Not all cases of CLL require treatment at diagnosis. International Workshop on Chronic Lymphocytic Leukemia (iwCLL) had set defined criteria for initiation of treatment.
[Table 1] shows the criteria for treatment in diagnosed cases of CLL
Besides clinical staging, various biochemical markers influence disease prognosis. IGHV mutational status, del(17p) and/or TP53 mutations, and serum β2-microglobulin are the most relevant prognostic parameters. High-risk CLL is usually defined, at least in part, by a genetic aberration of the TP53 gene (ie, del(17p) or TP53 mutation). in chemotherapy-naïve patients 5%–8% show a short arm of chromosome 17 deletion (17pdel) and 4–37% have TP53 mutation respectively. Among cases with confirmed del17p majority show mutation in TP53. Patients with TP53 mutations show marked resistance to genotoxic chemotherapies and have reduced overall survival.
Patients with del(11q) clone present with bulky lymphadenopathy, rapid progression, and reduced OS, though some of these prognostic factors were overcome by the use of chemoimmunotherapy., Trisomy 12 observed in 10%–20% of patients with CLL is associated with an intermediate prognosis. Most common mutation found in 55% of all diagnosed cases is del (13q) when present in isolation is associated with a relatively benign course of the disease.
CLL international prognostic index (CLL-IPI) and various other prognostic stratification systems have been proposed. CLL-IPI is one of the most commonly used prognostic scores including clinical stage, age, IGHV mutational status, serum β2-microglobulin, and the presence of del(17p) and/or TP53 mutations parameters as a weighted score. The score predicts time to therapy in patients, especially with early-stage disease. However, the impact of CLL-IPI on overall survival is still unproven.
Additionally, various other recurrent genetic mutations like MYD88, NOTCH1, ATM, SF3B1, FBXW7, POT1, CHD2, RPS15, IKZF3, ZNF292, ZMYM3, ARID1A, and PTPN1 have been identified and are being studied for their role in disease pathogenesis and prognostic impact.
Increased understanding of disease biology in CLL has paved way for various new therapeutic options. The relative 5-year survival for patients with CLL currently is near 86.9%.
Till recently, systemic chemoimmunotherapy (CIT) was the standard of care for frontline management of CLL. The CIT regimens of fludarabine/cyclophosphamide/rituximab (FCR) and bendamustine/rituximab (BR) had excellent treatment response rates. However, CIT therapy is associated with significant myelosuppression and infectious complications, especially in patients with pre-existing co-morbidities. This has limited the use of CIT therapy in the elderly population. In addition, patients with a deletion 17p (del17p) or TP53 mutation (TP53mut) had inferior outcomes with CIT regimens due to rapid progression and shorter time to relapse. US Food and Drug Administration (FDA) approval and increasing accessibility to Bruton kinase inhibitors and the B-cell lymphoma-2 (BCL-2) inhibitor have redefined the frontline and second-line treatment. This approval has improved the treatment outcomes in patients with del17p/TP53mut, with a much higher OS than attained before with CIT.
Bruton tyrosine kinase inhibitor (BTKi)
RESONATE-2 a Phase III trial compared ibrutinib with chlorambucil and The Alliance trial A041202 trial compared ibrutinib with bendamustine -rituximab and ibrutinib with rituximab respectively. In the RESONATE-2 trial, the 5-year progression-free survival (PFS) was 70% for the ibrutinib arm and 12% with chlorambucil. The Alliance A041202 led to the preference for Ibrutinib in first-line settings. In this study 2-year, PFS of 87%, 88%, and 74% were reported with ibrutinib alone, ibrutinib rituximab, and BR respectively. This proved the superiority of ibrutinib-based therapy when compared to BR. The side effect profile of ibrutinib was reported manageable. Similarly, E1912 compared Ibrutinib-based therapy with fludarabine, cyclophosphamide, and rituximab (FCR) in treatment naïve patients aged <70 years. They also favored the use of ibrutinib over FCR.
The ELEVATE-TN study evaluated second-generation BTKi acalabrutinib in treatment naïve CLL patients. The study included patients older than 65 years or younger patients with comorbidities or renal dysfunction defined as a Cumulative Illness Rating Score [CIRS] of >6 or creatinine clearance [CrCl] <70 respectively. the randomized trial compared acalabrutinib, acalabrutinib with the anti-CD20 antibody obinutuzumab (A + G), and chlorambucil with anti-CD-20 obinutuzumab. (C + G). At 28.3 months of median follow-up, the 2-year PFS was 93%, 87%, and 46% for A + G, acalabrutinib alone, and C + G respectively. These lead to a preference for Ibrutinib and acalabrutinib over chemoimmunotherapy as initial therapy for most patients. Improved treatment outcomes including in high-risk settings, tolerable side effects, and oral route of treatment have made these agents preferred first-line treatment in untreated CLL patients irrespective of cytogenetics and molecular risk factors in all age groups. The limitations of these BTKis are infinite treatment duration, cardiovascular side effects including hypertension, cardiac arrhythmias, and increased bleeding risks, especially in patients on anticoagulants. These side effects were more marked with ibrutinib compared to acalabrutinib. Transient headache was unique toxicity seen with Acalabrutinib. Diarrhea and dryness of the skin were other noted toxicities. In the long-term results of the RESONATE-2 trial treatment discontinuations due to adverse effects were seen in 7% in years 0–1, 6% in years 1–2, 5% in years 2–3, 6% in years 3–4, and 1% in years 4–5 years respectively. As with other targeted therapies disease progression has been seen in CLL patients on BTKis. The acquisition of secondary mutations of BTK leading to impaired binding of the BTKi is the most common cause of resistance to BTKis. Acquired mutations in Cys481 or phospholipase C-γ2 have been reported in >80% of patients with disease progression on ibrutinib. The mechanisms of resistance are yet not fully understood.
BTKi based therapy is now being used as first-line therapy across many centers in the country. The introduction of biosimilars will reduce the treatment cost and increase the accessibility of these drugs. Though the efficacy of these biosimilars needs to be looked at.
Practical limitations faced in clinical practice
Higher cost of treatment, indefinite therapy. The increasing incidence of metabolic syndromes in India and other southeast Asian nations led to an increased risk of hypertension, and cardiovascular morbidity including coronary artery disease. We have lower educational status and relatively scarce health care facilities especially in rural India, regular monitoring for cardiovascular side effects and prompt treatment is problematic. Indefinite drug therapy leads to long-term non-adherence.
B cell lymphoma 2 (BCL2) Inhibitors
The other new approved drug in frontline settings for treatment in CLL patients is BCL2 inhibitor Venetoclax. CLL 14 study phase III randomized trial comparing venetoclax -obinutuzumab(V + G) with chlorambucil and obinutuzumab (C + G) showed a 24-month PFS of 88.2% (95% CI, 83.7 to 92.6) and 64.1% (95% CI, 57.4 to 70.8) in V + G v/s C + G arm. In this study higher rates of MRD negativity were also shown in V + G arm (75.5%,56.9%) compared to C + G (35.2%, 17.1%). This therapy was a finite duration therapy compared to indefinite therapy with BTKi. The most common grade 3 AEs were cytopenias, infections, and infusion reactions. Strict TLS prophylaxis was given
Venetoclax-based therapy is being opted for by many patients as it is a finite therapy with lesser-known cardiovascular side effects. Again, the major limitation is the high cost of the therapy.
Combining BTKi and BCL2 inhibitors
with the tremendous success seen with these new agents we now aim for deeper remission with a finite therapy. Many combination strategies which include BCL-2 inhibitors and BTKis, with or without anti-CD20 antibodies, are under study. Ibrutinib-Venetoclax has been studied. In a single-center phase 2 trial, the ibrutinib-venetoclax combination was given for 12 cycles; CR and CR with incomplete count recovery (CRi) rates of 88% CR were noted, and 61% of patients had uMRD. Similar findings were noted in a multicenter phase 2 trial (CAPTIVATE) in which 12 cycles of ibrutinib-venetoclax were given.
More studies will be required to determine whether time-limited treatment with these targeted agents can improve long-term outcomes and completely omit the CIT regimens in CLL.
Regimens BR and FCR still are among the first-line treatment options in specific clinical settings. FCR remains the first line in patients with age less than 65 years with mutated IGHV status without 17p deletion or TP53 mutation. And IGHV mutated status and absence of 17p deletion or TP53 mutation for BR. These regimens can be discussed as an option for this subgroup, with consideration of their toxicity profiles, duration of therapy, and cost of therapy with the potential for long-term remission.
Considerations for first-line therapy
Factors determining the frontline treatment of CLL, include patient factors including comorbidities, preference for duration of therapy, availability, and cost of therapy. As discussed before, CLL patients with high-risk features and UM- IGHV benefit from chemotherapy-free frontline regimens, so these options should be offered as the new standard of care to this group.
CIT therapy still holds promise in a set of patients as a limited-duration therapy.
BTKi or BCL2 inhibitors- how to choose?
Given high response rates with ibrutinib, acalabrutinib, and venetoclax, there is no obvious superior choice. The decision between BTKi and venetoclax-based therapy should depend on the experience of the provider and the preferences and comorbidities of the patient.
| Conclusion|| |
Now, with the availability of new safe, effective, and well tolerable therapy for CLL the therapeutic landscape of CLL has evolved dramatically. [Table 2]. compares the various therapeutic agents currently used in CLL management. There has been a considerable change in the approach to the treatment of CLL worldwide Developed nations are now moving away from the chemotherapy-based regimen. Questions remain regarding the choice of therapy and optimal combinations of newer therapeutic agents. In a resource-limited setting like ours, CIT offers a cheap and definite therapy and will still have a long way to go till the targeted therapies can become more affordable.
|Table 2: Comparing Reported Outcomes in commercially available first line CLL therapies|
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Conflicts of interest
There are no conflicts of interest.
| References|| |
GBD Results [Internet]. Institute for Health Metrics and Evaluation. [cited 2022 May 29]. Available from: https://vizhub.healthdata.org/gbd-results
. [Last accessed on 2022 Jun 10].
Chronic Lymphocytic Leukemia - Cancer Stat Facts [Internet]. SEER. [cited 2022 May 29]. Available from: https://seer.cancer.gov/statfacts/html/clyl.html
. [Last accessed on 2022 Jun 10].
Gunawardana C, Austen B, Powell JE, Fegan C, Wandroo F, Jacobs A, et al
. South asian chronic lymphocytic leukaemia patients have more rapid disease progression in comparison to white patients. Br J Haematol 2008;142:606-9.
Agrawal N, Naithani R, Mahapatra M, Panigrahi I, Kumar R, Pati HP, et al
. Chronic lymphocytic leukemia in india-a clinico-hematological profile. Hematology 2007;12:229-33.
Nair CN, Chougule A, Dhond S, Goyal R, Parikh PM, Pai S, et al
. Trisomy 12 in chronic lymphocytic leukemia–geographical variation. Leuk Res 1998;22:313-7.
Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES The 2008 WHO classification of lymphoid neoplasms and beyond: Evolving concepts and practical applications. Blood 2011;117:5019-32.
Johnston JB, Parikh SA, Gibson SB, Kenderian SJ, Kay NE Wintrobes clinical hematology. 14th ed. Philadelphia: Wolters Kluwer; 2018. p. 1948-85.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al
. Iwcll guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018;131:2745-60.
Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al
. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000;343:1910-6.
Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al
; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: A randomised, open-label, phase 3 trial. Lancet 2010;376:1164-74.
Allan JN, Shanafelt T, Wiestner A, Moreno C, O’Brien SM, Li J, et al
. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: A pooled analysis from four clinical trials. Br J Haematol 2022;196:947-53.
Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, et al
. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 2018;379: 2517-28.
Shanafelt TD, Wang XV, Kay NE, Hanson CA, O’Brien S, Barrientos J, et al
. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. New England Journal of Medicine 2019;381:432-43. Available from: https://doi.org/10.1056/NEJMoa1817073
Sharman JP, Banerji V, Fogliatto LM, Herishanu Y, Munir T, Walewska R, et al
. ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL). Blood 2019;134(Supplement_1):31. Available from: https://doi.org/10.1182/blood-2019–128404
Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, et al
. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia 2020;34:787-98.
Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A, et al
. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol 2017;35:1437-43.
Misra A, Khurana L The metabolic syndrome in south asians: Epidemiology, determinants, and prevention. Metab Syndr Relat Disord 2009;7:497-514.
Al-Sawaf O, Zhang C, Tandon M, Sinha A, Fink AM, Robrecht S, et al
. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): Follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2020;21:1188-200.
Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G, et al
. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med 2019;380:2095-103.
Wierda WG, Allan JN, Siddiqi T, Kipps TJ, Opat S, Tedeschi A, et al
. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: Primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study. J Clin Oncol 2021;39:3853-65.
Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, et al
. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 2019;380:2225-36.
Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Kamdar MK, et al
. Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: Elevate-TN four-year follow up. J Clin Oncol2021;39(15_suppl):7509.
[Table 1], [Table 2]