Safety and Efficacy of BeEAC as a Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Relapsed/Refractory Lymphomas

VO Sarzhevskii, AA Samoilova, VYa Melnichenko, YuN Dubinina, NE Mochkin, DS Kolesnikova, DA Fedorenko, EG Smirnova, AE Bannikova, VS Bogatyrev

NI Pirogov Russian National Medical Center of Surgery, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

For correspondence: Anastasiya Aleksandrovna Samoilova, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203; Tel.: +7(495)603-72-17; e-mail: samoylove03@gmail.com

For citation: Sarzhevskii VO, Samoilova AA, Melnichenko VYa, et al. Safety and Efficacy of BeEAC as a Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Relapsed/Refractory Lymphomas. Clinical oncohematology. 2020;13(2):185–92 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-185-192


ABSTRACT

Aim. To assess the safety and efficacy of BeEAC as a conditioning regimen prior to autologous hematopoietic stem cell transplantation (auto-HSCT) in relapsed and primary resistant lymphomas (ClinicalTrials.gov NCT03315520).

Materials & Methods. The trial included 113 patients with Hodgkin’s (HL) and non-Hodgkin’s lymphomas (NHL). The patients were included into the protocol during the period from February 2016 to June 2018. Median follow-up was 26 months. Among the patients there were 58 men and 55 women. Median age was 33 years (range 18–65 years). In 72 patients HL and in 41 patients NHL (in 15 diffuse large B-cell lymphoma, in 8 primary mediastinal (thymic) large B-cell lymphoma, in 10 mantle cell lymphoma, in 4 peripheral T-cell lymphoma unspecified, and in 4 patients follicular lymphoma) were diagnosed. BeEAC conditioning regimen consisted of administering 160–200 mg/m2 bendamustine in increasing doses on Day –6 and Day –5 combined with fixed doses of 200 mg/m2 cytarabine every 12 hours, 200 mg/m2 etoposide, and 140 mg/kg cyclophosphamide from Day –4 to Day –1.

Results. In phase 1, when bendamustine dose was increased from 160 mg/m2 to 200 mg/m2, no dose-limiting toxicity was observed. Afterwards patients received 200 mg/m2 of bendamustine. The assessment of tumor status in 2–3 months after auto-HSCT showed that complete remission was achieved in 62.9 % (n = 71) of patients, partial remission in 16.8 % (n = 19) of patients, stabilization in 0.9 % (n = 1) of patients and progression in 15 % (n = 17) of patients. In 5 patients the treatment effect was not assessed. Early post-transplant mortality (up to Day +30) was 3.6 % (n = 4) and overall mortality within the follow-up period (median 26 months) was 23 % (n = 26). Overall survival in the whole cohort of patients for 12, 18, 24, and 36 months was 88 %, 82 %, 78 %, and 64 %, respectively, and progression-free survival was 61 %, 57 %, 54 %, and 40 %, respectively.

Conclusion. BeEAC proved to be relatively safe when applied as a conditioning regimen prior to auto-HSCT in HL and NHL patients. Further data need to be collected to finally assess the efficacy of this regimen and to conduct a retrospective comparative analysis of it and other conditioning regimens in lymphomas.

Keywords: high-dose chemotherapy, autologous hematopoietic stem cell transplantation, conditioning regimens, bendamustine, toxicity.

Received: September 6, 2019

Accepted: March 3, 2020

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Bendamustine in the Treatment of Relapsed/Refractory Hodgkin’s Lymphoma: Literature Review and Clinical Experience

SS Shklyaev, NA Falaleeva, TI Bogatyreva, AYu Terekhova, MA Danilova

AF Tsyb Medical Radiological Research Centre, branch of the NMRC of Radiology, 4 Koroleva str., Kaluga Region, Obninsk, Russian Federation, 249036

For correspondence: Stanislav Sergeevich Shklyaev, MD, PhD, 4 Koroleva str., Kaluga Region, Obninsk, Russian Federation, 249036; Tel.: +7(484)399-30-31; e-mail: staniss1@yahoo.com

For citation: Shklyaev SS, Falaleeva NA, Bogatyreva TI, et al. Bendamustine in the Treatment of Relapsed/Refractory Hodgkin’s Lymphoma: Literature Review and Clinical Experience. Clinical oncohematology. 2020;13(2):136–49 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-136-149


ABSTRACT

Aim. To assess the efficacy of bendamustine combined with dexamethasone in the treatment of relapsed/refractory Hodgkin’s lymphoma (HL).

Materials & Methods. The article provides an updated review of literature as well as the data of prospective observational clinical trial in 47 HL patients (17 men and 30 women aged 20–65 years, median age 36 years) with relapses after standard and high-dose chemotherapy with autologous hematopoietic stem cell transplantation. The therapy regimen included 120 mg/m2 of bendamustine IV on Days 1 and 2 and 20 mg of oral dexamethasone from Day 1 to Day 4. Retreatment was administered 21 days after the start of the previous one. Radiotherapy was applied only to the regions of massive relapsed lesions and bone destructions with pain syndrome.

Results. From April 2011 to September 2017 all 47 patients received 149 bendamustine + dexamethasone therapy regimens with the overall response of 57 % (complete response 27 %, partial response 30 %). Disease progression on therapy was reported in 20 (43 %) patients, its incidence was the highest after the first (n = 8) or the second cycle (n = 4). In the group of 27 patients with overall response 19 (70 %) patients showed new relapses. In these cases the treatment-free period was from 8 to 31 months (median 11 months). The repeated administration of 57 bendamustine + dexamethasone therapy regimens in 12 out of 47 patients achieved clinical effect for 4–36 months (median 6 months). After the first failure of bendamustine-based therapy 13 patients were treated with brentuximab vedotin and nivolumab, the new salvage therapy drugs. With median follow-up of 22 months (range 1–69 months) median overall survival (OS) and time to the next progression were 35 and 10 months, respectively, in all patients. Multivariate analysis showed that OS was unfavorably affected only by B-symptoms on bendamustine + dexamethasone administration (= 0.046), and the time to the next progression was shorter in the presence of B-symptoms (= 0.017) and in histological variant “nodular sclerosis type II” (= 0.006).

Conclusion. Bendamustine + dexamethasone therapy is a relatively low-toxic and effective method of life prolongation in HL patients with chemotherapy-refractory tumors and recurrent relapses, provided no B-symptoms occur by the start of antitumor therapy.

Keywords: Hodgkin’s lymphoma, bendamustine, chemotherapy-refractory disease, relapses.

Received: December 15, 2019

Accepted: March 20, 2020

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Minimal Residual Disease and IGHV-Genes Mutational Status as the Main Predictors of Response to Bendamustine-Rituximab Therapy in Previously Untreated Chronic Lymphocytic Leukemia

YuV Mirolyubova, EA Stadnik, VV Strugov, TO Andreeva, TS Nikulina, YuV Virts, PA Butylin, AG Rumyantsev, AYu Zaritskey

VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Yuliya Vladimirovna Mirolyubova, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; e-mail: juli9702@yandex.ru

For citation: Mirolyubova YuV, Stadnik EA, Strugov VV, et al. Minimal Residual Disease and IGHV-Genes Mutational Status as the Main Predictors of Response to Bendamustine-Rituximab Therapy in Previously Untreated Chronic Lymphocytic Leukemia. Clinical oncohematology. 2018;11(2):167–74.

DOI: 10.21320/2500-2139-2018-11-2-167-174


ABSTRACT

Background. In patients with chronic lymphocytic leukemia (CLL) the eradication of minimal residual disease (MRD) is a prognostic factor of overall survival (OS) and progression-free survival (PFS). IGHV mutational status has also independent prognostic value.

Aim. To analyse the impact of mutational status and MRD eradication in CLL patients after first-line standard BR (bendamustine + rituximab) immunochemotherapy.

Materials & Methods. The prospective study included patients with immunophenotypically confirmed CLL who had not previously received anticancer therapy. All patients were treated by BR combination from 2012 to 2015. MRD level was determined in 109 patients after completing the 3rd and the 6th treatment courses. IGHV mutational status data were available for 98 patients. IGHV mutational status was evaluated in accordance with ERIC recommendations. MRD was assessed by standardized method of 4-color flow cytometry.

Results. MRD negativity was achieved in 37 (34 %) out of 109 patients. MRD eradication correlated with the best PFS (= 0.04). IGHV mutational status had a statistically significant impact on PFS (= 0.02). In patients with MRD-negative response and IGHV mutation no unfavorable events occurred during the period of monitoring. Conversely, PFS rates in MRD-negative patients having no IGHV mutation and in MRD-positive patients with mutation were significantly worse. MRD eradication resulted in statistically significant improvement of PFS rates after completing 3 treatment courses, compared with the cases with MRD persistence regardless of residual malignant clone level (= 0.01).

Conclusion. BR therapy as first-line treatment statistically improved PFS in patients who achieved MRD-negative remission after completing the 3rd treatment course. PFS was significantly higher in MRD-negative patients with IGHV mutation after 6 treatment courses. MRD negativity resulting from 6 BR therapies in patients having no IGHV mutation was not accompanied by PFS improvement. It follows that by itself MRD negativity cannot be considered to be a universal prognostic factor.

Keywords: chronic lymphocytic leukemia, minimal residual disease, bendamustine, rituximab, BR, IGHV, mutational status.

Received: December 29, 2017

Accepted: February 27, 2018

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Effect of IGHV Gene Mutation Status and BCR Structure Stereotypy on Effectiveness of BR Regimen in First-Line Therapy of Chronic Lymphocytic Leukemia

VV Strugov1, EA Stadnik1,2, AM Rumyantsev1, TO Andreeva1, YuV Virts1, YuV Mirolyubova1, PA Butylin1, AYu Zaritskey1,2

1 Federal Almazov North-West Medical Research Centre, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

2 Internal medicine clinic, Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Vladimir Vladimirovich Strugov, staff scientist, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel: +7(812)702-37-49; e-mail: strugov@almazovcentre.ru

For citation: Strugov VV, Stadnik EA, Rumyantsev AM, et al. Effect of IGHV Gene Mutation Status and BCR Structure Stereotypy on Effectiveness of BR Regimen in First-Line Therapy of Chronic Lymphocytic Leukemia. Clinical oncohematology. 2017;10(2):141–9 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-141-149


ABSTRACT

Background & Aims. The IGHV gene mutation status is a constant biological feature of tumor cells in chronic lymphocytic leukemia (CLL). This parameter is an important predictor of the efficacy of immunochemotherapy. It was included into the CLL international prognostic index CLL-IPI developed recently. The aim is to evaluate the prognostic significance of the BR regimen in patients with different variants of the B-cell receptor (BCR) structure.

Methods. The study examined immediate and delayed treatment outcomes for 183 CLL patients included in a Russian, prospective, observational BEN-001 trial (NCT02110394). The median age was 61 years (range: 35–79); 53/179 (29.6 %) patients were older than 65; and 14/179 (7.8 %) patients were older than 75. Prevalence of males (110/179, 61.5 %) in the male/female ratio (1.6:1.0) was observed. Most patients had advanced disease: Binet B 116/173 (67 %) or Binet C 38/173 (22 %). The patients received the first-line therapy according to the BR regimen at standard doses in 36 hematological institutions in the Russian Federation over the period from 2012 until 2015. The genome DNA isolated from mononuclear leukocytes in the peripheral blood was used to assess the mutation status of the IGHV-genes.

Results. The study demonstrated that unmutated CLL (≥ 98 % of homology to germline gene) is associated with worsening of the event-free and overall survival rates most of all; at that, the complete remission rate and the MRD-free survival rate were the same.

Conclusion. It is reasonable to analyze the IGHV mutation status in all patients prescribed with the BR regimen as the first-line therapy.

Keywords: chronic lymphocytic leukemia, CLL, bendamustine, rituximab, BR, IGHV, mutation status, stereotypy.

Received: January 8, 2017

Accepted: January 26, 2017

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High-Dose Chemotherapy for Grade 3B Relapsed Follicular Lymphoma with Deletions of Loci of BCL6 (3q27) and TP53 (17p13) Genes: Case Report and Literature Review

EE Zvonkov, NG Gabeeva, MV Firsova, EV Moiseeva, VV Troitskaya, LA Kuz’mina, TN Obukhova, AM Kovrigina, EN Parovichnikova, VG Savchenko

Hematology Research Center under the Ministry of Health of the Russian Federation, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Nelli Georgievna Gabeeva, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-48-10; e-mail: dr.gabeeva@gmail.com

For citation: Zvonkov EE, Gabeeva NG, Firsova MV, et al. High-Dose Chemotherapy for Relapsed Follicular Lymphoma Grade 3B with Deletions of Loci of BCL6 (3q27) and TP53 (17p13) Genes: Case Report and Literature Review. Clinical oncohematology. 2015;8(1):36–43 (In Russ).


ABSTRACT

Background. The article describes a rare case of grade 3В follicular lymphoma (FL) with a nodular-diffuse growth; it also presents a literature review. Grade 3В follicular lymphoma with a nodular-diffuse growth is a rare lymphoid neoplasm, and no optimal therapeutic strategies have been developed for it. In addition to the absence of the classic t(14;18), combined deletions of 17p13 (TР53 gene locus) and 3q27 (BCL6 gene locus) are observed in a very few cases. This combination may negatively affect the FL prognosis. The unique ability of bendamustine to induce ТР53-independent apoptosis offers new opportunities for the high-dose chemotherapy of lymphomas.

Objective. To evaluate efficacy and tolerance of the ВеЕАМ conditioning regimen using high-dose bendamustine followed by autologous HSCT in a patient with 3B FL relapse and combined 17p13 and 3q27 deletion.

Methods. A 58-year-old man was diagnosed with 3B grade FL. After 8 R-CHOP courses and a two-year maintenance therapy with Rituximab, he developed a generalized enlargement of lymph nodes, and a neoplasm in left liver lobe. A liver biopsy confirmed the relapse of grade 3B FL with a nodular-diffuse growth and a high Ki-67 level (60 %). Cytogenetic analysis identified 17p13 and 3q27 deletions.

Results. Four courses of anti-relapse therapy were performed (2 — DHAP and 2 — ICE). PET scanning showed a complete regression in lymph nodes, whereas the size of the focus in the liver and the rate of accumulation of radiopharmaceuticals in it remained unchanged. ВеЕАМ conditioning regimen (bendamustine 600 mg) followed by autologous HSCT were performed. 46 days after the autologous HSCT, the tumor focus in the liver was PET-negative. The remission retained for 10 months.

Conclusions. Further study of the efficacy of high-dose bendamustine in the therapy of aggressive lymphoid tumors with TP53 mutation seems promising.


Keywords: follicular lymphoma, TP53-independent apoptosis, bendamustine.

Received: October 24, 2014

Accepted: October 27, 2014

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Role of Bendamustine in Treatment of Multiple Myeloma

O.M. Votyakova

N.N. Blokhin Russian Cancer Research Center of RAMS, Moscow, Russian Federation

For citation: Votyakova O.M. Role of Bendamustine in Treatment of Multiple Myeloma. Klin. onkogematol. 2014; 7(3): 301–10 (In Russ.).

ABSTRACT

Bendamustine is an antineoplastic drug with a double mechanism of action combining the properties of alkylating compound and purine analog; it has a promising activity in multiple myeloma (MM). In 2013, Bendamustine (Ribomustin) was registered in Russia for treatment of patients older than 65 years of age with newly diagnosed ММ who are not eligible for high dose chemotherapy (HDC) with autologous transplantation of hemopoetic stem cells and who have clinical signs of neuropathy which impede the use of thalidomide and/or bortezomib. The review presents data on the product efficacy and safety both as monotherapy and in combination with glucocorticoids and target therapy (bortezomib, thalidomide, lenalidomide), in newly diagnosed and relapsed MM patients. The presented data permit to recommend bendamustine combined with glucocorticoids and novel drugs for MM patients with relapses and as the first line therapy in some patients with polyneuropathy who are not eligible for HDC with autologous transplantation of hemopoetic stem cells.


Keywords: multiple myeloma, bendamustine, ribomustin.

Address correspondence to: omvtk@yandex.ru

Accepted: May 23, 2014

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Pulmonary MALT-lymphoma: case report and literature review

A.K. Morozova, N.G. Gabeeva, and E.E. Zvonkov

Hematology Research Center, RF Ministry of Health, Moscow, Russian Federation


ABSTRACT

This article presents a rare case of pulmonary MALT-lymphoma and literature review. An elderly patient with pulmonary MALT lymphoma was successfully treated according to R-B (rituximab + bendamustine) chemotherapy program. After 6 R-B courses, sustained remission with minimal toxicity and good tolerability was achieved.


Keywords: pulmonary MALT-lymphoma, chemotherapy, bendamustine

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REFERENCES
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  22. Rummel M.J., Kaiser U., Balser C. Bendamustine Plus Rituximab Versus Fludarabine Plus Rituximab In Patients with Relapsed Follicular, Indolent and Mantle Cell Lymphomas — Final Results of the Randomized Phase III Study NHL 2-2003 on Behalf of the StiL (Study Group Indolent Lymphomas, Germany). ASH Annual Meeting Abstracts 2010; 116: 856.
  23. Rummel M.J., Niederle N., Maschmeyer G. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 noninferiority trial. Lancet, Early Online Publication, 20 February 2013. doi: 10.1016/ S0140-6736(12)61763.

Hodgkin’s lymphoma and a “new old” bendamustine

S.S. Shklyaev, and V.V. Pavlov

Medical Radiological Research Center, RF Ministry of Health, Obninsk, Russian Federation


ABSTRACT

Hodgkin’s lymphoma is a malignant tumor that eventually turned from a fatal incurable to successfully curable disease after primary treatment in the vast majority of cases. However, the prognosis for patients with refractory and relapsed disease is not infrequently dismal and life-threatening, especially if the tumor continues progressing after high-dose chemotherapy with autologous stem cell transplantation or, in some instances, even after allogeneic stem cell grafting. Bendamustine is a “new old” cytostatic agent that can be effectively applied for treating this group of patients. Our literature review highlights a variety of relevant options in treatment of Hodgkin’s lymphoma using bendamustine.


Keywords: Hodgkin’s lymphoma, refractory and relapsed disease, treatment, bendamustine.

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REFERENCES

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  1. D’Elia G.M., De Anelis F., Breccia M. et al. Efficacy of bendamustine as salvage treatment in an heavily pre-treated Hodgkin lymphoma. Leuk. Res. 2010; 34(11): e300–1.
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  11. Регистрация клинического исследования в Европейском медицинском агентстве (European Medicines Agency): EudraCT #2008-002736-15. [Registratsiya klinicheskogo issledovaniya v Evropeyskom meditsinskom agentstve (European Medicines Agency) [Registration of a clinical study in European Medicines Agency]. EudraCT #2008-002736-15.]
  1. Kath R., Blumenstengel K., Fricke H.J. et al. Bendamustine, vincristine; prednisolone (BOP) in therapy of advanced low-grade non-Hodgkin lymphoma. Dtsch. Med. Wochenschr. 2001; 126(8): 198–202.
  2. Friedberg J.W., Vose J.M., Kelly J.L. et al. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood 2011; 117(10): 2807–12.
  3. Visco C., Castegnaro S., Chieregato K. et al. The cytotoxic effects of bendamustine in combination with cytarabine in mantle cell lymphoma cell lines. Blood Cells. Mol. Dis. 2012; 48(1): 68–75.
  4. Yong H.X., Linn Y.C., Ong K.H. et al. Chemoimmunotherapy with bendamustine hydrochloride and alemtuzumab demonstrates synergism in T-prolymphocytic leukemia. Leuk. Res. 2012; 36(8): e163–5.
  5. Alaikov T., Konstantinov S.M., Tzanova T. et al. Antineoplastic and anticlastogenic properties of curcumin. Ann. N. Y. Acad. Sci. 2007; 1095: 355–70.
  6. Lentzsch S., O’Sullivan A., Kennedy R.C. et al. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood 2012; 119(20): 4608–13.
  7. Loibl S., Doering G., Muller L. et al. Phase II Study with Weekly Bendamustine and Paclitaxel as First- or Later-Line Therapy in Patients with Metastatic Breast Cancer: RiTa II Trial. Breast Care (Basel). 2011; 6(6): 457–61.
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Chronic lymphocytic leukemia and renal cell carcinoma: literature review and case reports

B.T. Dzhumabaeva, E.A. Nikitin, I.B. Kaplanskaya, E.E. Zybunova, L.S. Biryukova,

FSBI «Haematological Research Center» Russian Ministry of Health, Moscow, Russian Federation


ABSTRACT

Renal cell carcinoma which had acceded to the CLL, induces the progression of lymphatic tumours and contributes to the rapid development of renal failure. The surgical removal of the affected renal not eliminates the progression of CLL. Monotherapy by alkylating agents is not effective, while bendamustine therapy allows to reach the positive result.


Keywords: Chronic lymphocytic leukemia (CLL), Renal cell carcinoma, renal failure, bendamustine.

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