Practical Aspects of the Use of Carfilzomib in Multiple Myeloma

SV Semochkin1,2, GN Salogub3, SS Bessmeltsev4, KD Kaplanov5

1 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

2 Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182

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

4 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

5 Volgograd Regional Clinical Oncology Dispensary No. 1, 78 Zemlyachki str., Volgograd, Russian Federation, 400138

For correspondence: Prof. Sergei Vyacheslavovich Semochkin, MD, PhD, 3 Pekhotnaya str., Moscow, Russian Federation, 123182; Tel./fax: +7(495)369-00-36; e-mail: semochkin_sv@rsmu.ru

For citation: Semochkin SV, Salogub GN, Bessmeltsev SS, Kaplanov KD. Practical Aspects of the Use of Carfilzomib in Multiple Myeloma. Clinical oncohematology. 2019;12(1):21–31.

DOI: 10.21320/2500-2139-2019-12-1-21-31


ABSTRACT

Carfilzomib (Kyprolis®, Amgen), a second-generation proteasome inhibitor, is capable of covalent bonding and irreversible inhibition of the 20S proteasome chymotrypsin-like activity. In 2016 this drug was approved in Russia for monotherapy of relapsed refractory multiple myeloma (MM) and in combination with lenalidomide and dexamethasone (KRd) or only with dexamethasone (Kd) for treatment of patients with relapsed MM after at least one line of prior therapy. The present review outlines mechanism, clinical efficacy, and adverse effects of carfilzomib according to the data of a phase II (monotherapy) trial and two key randomized phase III (carfilzomib combined with other drugs) trials. The ASPIRE trial demonstrated that adding carfilzomib to the combination of lenalidomide and dexamethasone (KRd) significantly improves progression-free survival (PFS) compared with the Rd original regimen (median 26.3 vs. 17.6 months; hazard ratio [HR] 0.69; = 0.0001). Median overall survival (OS) was 48.3 months (95% confidence interval [95% CI] 42.4–52.8 months) for KRd vs. 40.4 months (95% CI 33.6–44.4 months) for Rd (HR 0.79; = 0.0045). The ENDEAVOR trial showed that as compared with combination of bortezomib and dexamethasone (Vd) the carfilzomib + dexamethasone (Kd) regimen significantly improves PFS (median 18.7 vs. 9.4 months; HR 0.53; < 0.0001) and OS (47.6 vs. 40.0 months; HR 0.79; = 0.010) as well. The present review also discusses how carfilzomib is to be used in special patient groups (with renal failure and high cytogenetic risk).

Keywords: carfilzomib, proteasome inhibitor, lenalidomide, bortezomib, multiple myeloma, renal failure, cytogenetic risk.

Received: May 12, 2018

Accepted: December 28, 2018

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Erythrodermic Mycosis Fungoides: The Algorithm of Diagnosis and Treatment

OYu Olisova1, AA Sydikov2, IN Chuprov3, LG Gorenkova4, SA Chernysh5, VA Doronin6, EV Grekova1

1 IM Sechenov First Moscow State Medical University, 8 bld. 2 Trubetskaya str., Moscow, Russian Federation, 119991

2 Saint-Petersburg State Pediatric Medical University, 2 Litovskaya str., Saint Petersburg, Russian Federation, 194100

3 II Mechnikov North-Western State Medical University, 41 Kirochnaya str., Saint Petersburg, Russian Federation, 191015

4 National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

5 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

6 Municipal Clinical Hospital No. 40, 7 Kasatkina str., Moscow, Russian Federation, 129301

For correspondence: Ekaterina Vladimirovna Grekova, 8 bld. 2 Trubetskaya str., Moscow, Russian Federation, 119991; e-mail: grekova_kate@mail.ru

For citation: Olisova OYu, Sydikov AA, Chuprov IN, et al. Erythrodermic Mycosis Fungoides: The Algorithm of Diagnosis and Treatment. Clinical oncohematology. 2018;11(4):295–302.

DOI: 10.21320/2500-2139-2018-11-4-295-302


ABSTRACT

Erythrodermic mycosis fungoides (eMF) is an atypical severe form of mycosis fungoides resulting from persistent and treatment-resistant disease. eMF manifests as generalized skin bluish lesions, intense itching, secondary lymphadenopathy, and significant deterioration of quality of life. A differential diagnostic algorithm for various forms of erythrodermia is suggested. The paper presents a clinical case of eMF with spots and plaques that skipped the tumor stage. Experience of eMF treatment using vorinostat, gemcitabine, doxorubicin, and alemtuzumab is described.

Keywords: erythrodermic mycosis fungoides, cutaneous lymphoma, diagnostic algorithms, vorinostat.

Received: May 8, 2018

Accepted: August 15, 2018

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Clinical Experience and Perspectives of Bosutinib Use in Patients with Chronic Myeloid Leukemia

VA Shuvaev1, OYu Vinogradova2,3,4, IS Martynkevich1, NV Novitskaya2, MS Fominykh1, SN Tsareva2, DI Shikhbabaeva2, MM Pankrashkina2,3, MV Chernikov2, NN Sharkunov2, II Zotova1, VYu Udal’eva1, EV Motyko1, SV Voloshin1,5,6

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

3 Dmitrii Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117198

4 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

5 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

6 II Mechnikov North-Western State Medical University, 41 Kirochnaya str., Saint Petersburg, Russian Federation, 191015

For correspondence: Ol’ga Yur’evna Vinogradova, MD, PhD, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Tel.: +7(495)945-97-61; e-mail: olgavinz@mail.ru.

For citation: Shuvaev VA, Vinogradova OYu, Martynkevich IS, et al. Clinical Experience and Perspectives of Bosutinib Use in Patients with Chronic Myeloid Leukemia. Clinical oncohematology. 2018;11(4):288–94.

DOI: 10.21320/2500-2139-2018-11-4-288-294


ABSTRACT

Aim. To evaluate the clinical experience of bosutinib use for treatment of chronic myeloid leukemia (CML) patients with intolerance and resistance to other tyrosine kinase inhibitors (TKI), as well as to compare the obtained results with the data of clinical trials.

Materials & Methods. The analysis was conducted on case history records of 51 CML patients (25 men and 26 women; median age was 56 years, range 28–86). By the beginning of bosutinib therapy 37 chronic phase, 8 acceleration phase, and 6 blast crisis patients were included in the study. Bosutinib was administered as secondline TKI treatment in 10 patients, as thirdline treatment in 18 patients, and as fourthline treatment in 23 patients. The causes for switching to bosutinib were poor tolerance of previous TKI therapy in 21 patients and resistance to previous TKI therapy in 30 patients.

Results. The median duration of bosutinib treatment was 6 months (range 1–50). Bosutinib toxicity profile and its tolerance in common clinical practice corresponded to the data of clinical trials. Because of adverse events the therapy was discontinued only in 5 (10 %) patients. Complete hematological response was 88 % (persistent response was maintained in 76 % of patients); complete cytogenetic response (CCyR) was 39 %, (persistent response in 37 % of cases); major molecular response (MMR) was 31 % (it was confirmed in 25 % of patients during the last follow-up visit). The efficacy of bosutinib in the real clinical setting was slightly higher compared to the results of clinical trials. This difference was associated with a disease phase, a reason for withdrawal of the previous TKI, line of treatment, BCRABL mutations, and the form of them. The therapy was continued in 22 (43 %) patients, most of them reached stable optimal response, both CCyR and MMR.

Conclusion. Bosutinib appears to be an acceptable alternative to other TKIs having its specific mechanisms of action and adverse events. The efficacy and safety of bosutinib proved in routine clinical practice are sufficient to recommend it for use in national hematology.

Keywords: chronic myeloid leukemia, bosutinib, target therapy, tyrosine kinase inhibitors, clinical practice.

Received: May 9, 2018

Accepted: August 10, 2018

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The Use of Pomalidomide in the Treatment of Relapsed/Refractory Multiple Myeloma in Patients with Renal Failure

IG Rekhtina, MV Nareiko, LP Mendeleeva

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Irina Germanovna Rekhtina, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-49-66; e-mail: rekhtina.i@blood.ru

For correspondence: Rekhtina IG, Nareiko MV, Mendeleeva LP. The Use of Pomalidomide in the Treatment of Relapsed/Refractory Multiple Myeloma in Patients with Renal Failure. Clinical oncohematology. 2018;11(4):283–7.

DOI: 10.21320/2500-2139-2018-11-4-283-287


ABSTRACT

The present review includes data on efficacy and safety of pomalidomide, an immunomodulating 3rd generation drug used for treatment of relapsed and refractory multiple myeloma patients with renal failure. The results of multicenter randomized trials proved similar efficacy and comparable safety profile in patients with normal renal function and patients with moderate and/or severe renal failure. All patients received the standard starting dose. Pomalidomide dose needs to be reduced in response to hematological toxicity. The paper provides practical guidelines on the use of pomalidomide and treatment of adverse events adopted by consensus of international experts. Current approaches to multiple myeloma with renal failure, and the use of pomalidomide in particular, are demonstrated by means of a clinical case.

Keywords: multiple myeloma, pomalidomide, renal failure.

Received: March 28, 2018

Accepted: July 16, 2018

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REFERENCES

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PD-1 Blockade with Nivolumab as a New Immunotherapy for Classical Hodgkin’s Lymphoma

EA Demina

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Prof. Elena Andreevna Demina, MD, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; e-mail: drdemina@yandex.ru

For citation: Demina EA. PD-1 Blockade with Nivolumab as a New Immunotherapy for Classical Hodgkin’s Lymphoma. Clinical oncohematology. 2018;11(3):213–19.

DOI: 10.21320/2500-2139-2018-11-3-213-219


ABSTRACT

During the last two decades individualization of programmed treatment combined with intensified chemotherapy has proven to be effective treatment for the majority of classical Hodgkin’s lymphoma (cHL) patients. However, in 10–30 % of cases relapses and resistance to therapy still occur. Further intensification of therapy induces toxicity that leads to decrease in overall survival and quality of life. The standard second-line treatment with high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation (auto-HSCT) allows for the achievement of long-term 5-year progression-free survival only in 50–60 % of patients with relapsed disease and not more than 40–45 % of patients with refractory disease. Approximately 50 % of patients relapse after HDCT and auto-HSCT. The median overall survival of relapsed patients does not exceed 2 years. Allogeneic HSCT improves treatment results to some extent, but is not an optimal strategy in all patients. A search for new treatment options has been made to improve effectiveness of relapsed and refractory cHL treatment and to reduce toxicity of highly effective programs. А new CD30-targeted conjugate brentuximab vedotin was developed to use anti-CD30 monoclonal antibodies against a specific marker of tumor Reed-Sternberg cells allowing for the transfer of the highly effective antitumor compound of monomethyl auristatin E directly to tumor cells. This drug showed high effectiveness, although failed to provide a complete solution to the problem. The development of anti-PD1 antibody nivolumab opened up new opportunities for cHL treatment. This paper reviews literature information on pharmacological data and antitumor mechanisms of the drug as well as the results of significant international randomised studies.

Keywords: nivolumab, Hodgkin’s lymphoma, relapse, resistance, treatment.

Received: February 5, 2018

Accepted: April 30, 2018

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The Use of Brentuximab Vedotin in Relapsed/Refractory Hodgkin’s Lymphoma in the Kransnodar Region

OD Serdyuk, DA Yaskul’skii

Clinical Oncology Dispensary No. 1 of the Krasnodar region, 146 Dimitrova str., Krasnodar, Russian Federation, 350040

For correspondence: Ol’ga Dmitrievna Serdyuk, 146 Dimitrova str., Krasnodar, Russian Federation, 350040; Tel.: +7(918)441-08-33; e-mail: 7-18@mail.ru

For citation: Serdyuk OD, Yaskul’skii DA. The Use of Brentuximab Vedotin in Relapsed/Refractory Hodgkin’s Lymphoma in the Kransnodar Region. Clinical oncohematology. 2018;11(1):50-3.

DOI: 10.21320/2500-2139-2018-11-1-50-53


ABSTRACT

The treatment of relapsed/refractory Hodgkin’s lymphoma (HL) remains to be a challenging issue. The morbidity of HL is reported to increase in the Krasnodar region. While considerable progress in the treatment of HL has been achieved, the relapse rate still remains high. The standard second-line treatment allows for the disease control in only half of cases of relapsed HL. Until recently, however, relapses after autologous hematopoietic stem cell transplantation (autoHSCT) could be treated only by polychemotherapy aimed at slowing the tumor growth. The use of anti-CD30 conjugated monoclonal antibodies and cytotoxic agent was shown to control the relapsed disease after high dose chemotherapy followed by autoHSCT. The present study provides pharmacological characteristics of brentuximab vedotin, its antineoplastic mechanism as well as the author’s own clinical experience in the management of a female patient with HL after autoHSCT.

Keywords: Hodgkin’s lymphoma, brentuximab vedotin, targeted therapy, relapse.

Received: November 25, 2017

Accepted: January 8, 2018

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REFERENCES

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Ibrutinib in the Treatment of Relapsed Chronic Lymphocytic Leukemia

EA Stadnik, NS Timofeeva, VV Strugov, AYu Zaritskey

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

For correspondence: Elena Aleksandrovna Stadnik, PhD, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(921)575-54-55; e-mail: elena_stadnik@mail.ru

For citation: Stadnik EA, Timofeeva NS, Strugov VV, Zaritskey AYu. Ibrutinib in the Treatment of Relapsed Chronic Lymphocytic Leukemia. Clinical oncohematology. 2018;11(1):42–9.

DOI: 10.21320/2500-2139-2018-11-1-42-49


ABSTRACT

Aim. To estimate ibrutinib efficacy in the treatment of first early CLL relapses and in patients with ≥ 2 lines of preceding therapy. Analysis of treatment results in patients with del(17p) and monitoring of minimal residual disease (MRD) and ibrutinib safety profile.

Materials & Methods. The analysis included the results of ibrutinib treatment in 31 patients with CLL. Twenty eight patients were treated by bendamustine and fludarabine containing regimens. The median prior treatment lines were 2 (range 1–10). The indications for the treatment initiation were the first early relapse in 51 % of cases (n = 16) and a relapse after 2 and more lines of therapy in 49 % of cases (n = 15). Ibrutinib was administered in mono- (n = 15) and combined therapy (n = 14) as well as in the R-BAC scheme (n = 2). Using FISH analysis del(17p) was found in 9 patients (34 %).

Results. Within the median follow up of 18 months (range 7–42+) the overall survival (OS) rate was reported to be 87 %, and the progression-free survival (PFS) rate was 77 %. The maximum MRD after a year of ibrutinib treatment was observed in case of combination with immunochemotherapy (e.g., R-BAC). Within the period of 18 months OS rate was 100 %, in the patient group with first early relapses and 66 % in the group with a relapse after 2 and more therapy lines (= 0.02). Within the same examination period PFS was significantly higher (94 %) in the patient group with first early relapses compared to the previously treated patients (60 %) (= 0.034). The most common adverse events were grade 1–2 purpura (30 %), grade 1–2 diarrhea (10 %), atrial fibrillation paroxysms (10 %) and arterial hypertension (10 %). Severe infectious complications registered in 6 % (n = 3) patients were successfully solved in the course of combined antibacterial and antimycotic treatment.

Conclusion. Ibrutinib was shown to be effective drug for treatment of relapsed CLL. The OS and PFS values were more favourable in patients with first early relapses compared to the patients with relapses after ≥ 2 lines of therapy prior to ibrutinib treatment. The maximum elimination of the tumor clone was observed after combined ibrutinib/immunochemotherapy treatment. The tolerance of ibrutinib was reported to be satisfactory with acceptable toxicity profile. No mortality due to infection complications was observed.

Keywords: chronic lymphocytic leukemia, first early relapse, del(17p), ibrutinib, minimal residual disease.

Received: August 20, 2017

Accepted: November 16, 2017

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REFERENCES

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Current Opportunities for Treatment Optimization of Mycosis Fungoides and Sezary Syndrome

NG Chernova1, OA Kolomeitsev2

1 National Medical Hematology Research Center, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Natal’ya Gennad’evna Chernova, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-48-10; е-mail: ngchernova@mail.ru

For citation: Chernova NG, Kolomeitsev OA. Current Opportunities for Treatment Optimization of Mycosis Fungoides and Sezary Syndrome. Clinical oncohematology. 2018;11(1):34–41.

DOI: 10.21320/2500-2139-2018-11-1-34-41


ABSTRACT

Aim. To estimate vorinostat efficacy in patients with relapsed/refractory mycosis fungoides and Sezary syndrome.

Materials & Methods. The total of 21 patients with refractory and progressive mycosis fungoides and Sezary syndrome receiving vorinostat 400 mg once daily were followed up from 2014 to 2017. The median age was 62 years (range 34–79). The male to female ratio was 10/11. The median number of various regimens of pre-study systemic treatment was 4 (range 1–7). Progressive disease were observed in 85,7 % of patients before administration of vorinostat and after mono- and polychemotherapy.

Results. The study group included 15 patients with mycosis fungoides and 6 patients with Sezary syndrome. Early stages of primary cutaneous T-cell lymphoma were diagnosed in 4 patients, the advanced stages in 17 patients. Seventeen patients received vorinostat treatment in monoregime; 4 patients were administered with vorinostat in combination with methotrexate or α-interferon. The median duration of vorinostat therapy was 6 months (range 1–38). Stabilization of the disease was observed in 47.6 % of cases, response to treatment in 38.1 % of cases (with 5 cases of complete response and 3 cases of partial response), and 14.3 % of patients had progression of the disease. The decrease of skin itching was reported in 38.1 % of patients; skin itching completely resolved in 28.6 % of cases. The adverse events required the vorinostat dose adjustment in 3 cases and treatment discontinuation in 3 cases. The total of 9 patients continue to receive vorinostat.

Conclusion. Vorinostat treatment was shown to be effective in patients with refractory and advanced mycosis fungoides and Sezary syndrome not responding to various types of external, mono- and polychemotherapy. The therapy with vorinostat was associated with higher life expectancy and improved quality of life.

Keywords: vorinostat, mycosis fungoides, Sezary syndrome, refractory and advanced stages, primary cutaneous T-cell lymphoma.

Received: August 18, 2017

Accepted: December 1, 2017

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