BONE MARROW TRANSPLANTATION

High-Dose Chemotherapy and Autologous Stem Cells Transplantation for Relapsed/Refractory Hodgkin’s Lymphoma. Is There an Equal Right to Life?

BONE MARROW TRANSPLANTATION , , , ,

N.V. Zhukov1,2, A.G. Rumyantsev1, A.L. Uss3, N.F. Milanovich3, V.V. Ptushkin1, B.V. Afanasyev4, N.B. Mikhaylova4, V.B. Larionova5, E.A. Demina5, E.E. Karamanesht6, N.G. Tyurina7, M.A. Vernyuk7, A.D. Kaprin7

1 Dmitrii Rogachev Federal Scientific Clinical Centre of Pediatric Hematology, Oncology and Immunology under the RF MH, Moscow, Russian Federation

2 N.I. Pirogov Russian National Research Medical University, Moscow, Russian Federation

3 National Center for Hematology and Bone Marrow Transplantation, Minsk, Belarus

4 R.M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation under I.P. Pavlov State Medical University, Saint Petersburg, Russian Federation

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

6 Kyiv Center for Bone Marrow Transplantation, Kyiv, Ukraine

7 P.A. Hertsen Moscow Oncological Research Institute, Moscow, Russian Federation

For citation: Zhukov N.V., Rumyantsev A.G., Uss A.L., Milanovich N.F., Ptushkin V.V., Afanas’ev B.V., Mikhailova N.B., Larionova V.B., Demina E.A., Karamanesht E.E., Tyurina N.G., Vernyuk M.A., Kaprin A.D. High-Dose Chemotherapy and Autologous Stem Cells Transplantation for Relapsed/Refractory Hodgkin’s Lymphoma. Is There an Equal Right to Life? Klin. onkogematol. 2014; 7(3): 317–26 (In Russ.).

ABSTRACT

Aim. Hodgkin’s lymphoma (HL) patients with primary refractory (PRef) course of disease or relapses refractory to the previous 2nd line therapy (RRel) often are not given high-dose chemotherapy with autologous stem cell support (ASCS), and this refuse is motivated by its poor efficacy and high toxicity in this population. The objective of this study was to evaluate the efficacy and safety of ASCS in this patient population.

Materials and methods. 372 patients with Hodgkin’s lymphoma undergoing ASCS between 01.1990 and 06.2013 were included in the trial. The reason for ASCS was: primary refractory disease in 132 (35.5 %) patients, relapse of the disease resistant to II line chemotherapy (refractory relapse) in 81 (22 %). The remaining 159 patients (42.5 %) either had a relapse for which they received no II line chemotherapy (a relapse with untested sensitivity) or a relapse that proved to be sensitive to previously performed II line therapy (sensitive relapse). These patients were assigned to a chemosensitive HL group.

Results. With a median follow-up of 51 months, the overall survival rate (OS) and the relapse-free survival rate (RFS) did not differ significantly between patients with RRel, PRef and chemosensitive HL group (p > 0.05). Only freedom from treatment failure survival (FFTS) was significantly worse in patients with PRef HL (5-yrs EFS 42 % vs 58 % in patients with RRel vs 60 % in patients with chemosensitive HL group; p = 0.004). 100-day mortality mostly caused by ASCS toxicity also did not differ significantly between groups (p = 0.2). Irrespectively of primary reason for ASCS, long-term ASCS results significantly depended on response to the cytoreductive therapy. The effect of the cytoreductive therapy was assessed in 309 patients. When patients achieved complete, marked partial or partial remission, the 5-year overall survival rate, FFTS, and relapse-free survival rate was 78 %, 64 %, and 68 %, respectively. In patients with stabilization or progression of disease due to the cytoreductive therapy, these parameters were equal to 33 %, 24 % и 52 %, respectively (p < 0.001 for OS and FFTS, p = 0.005 for RFS).

Conclusion. In patients with primary refractory and refractory relapse of HL, ASCS has acceptable efficacy and early mortality which is comparable to that observed in patients with chemosensitive Hodgkin’s lymphoma, thus permitting to consider ASCS a potential therapeutic approach in patients with primary refractory disease and resistant relapses of Hodgkin’s lymphoma. Irrespectively of the initial disease course, the tumor response to the cytoreductive therapy is the most important predictive factor for the long-term ASCS results.

Keywords: Hodgkin’s lymphoma, high-dose chemotherapy, autologous hematopoietic stem cells transplantation, primary resistance, resistant relapse.

Address correspondence to: zhukov.nikolay@rambler.ru

Accepted: April 13, 2014

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Haploidentical hematopoietic stem cell transplantation in children with acute myeloid leukemia: evolution of method and our data

BONE MARROW TRANSPLANTATION , ,

N.N. Subbotina, I.S. Dolgopolov, A.V. Popa, V.K. Boyarshinov, R.I. Pimenov, and G.L. Mentkevich

Pediatric Oncology and Hematology Research Institute, N.N. Blokhin Russian Cancer Research Center, RAMS, Moscow, Russian Federation

ABSTRACT

This article presents the results of haploidentical stem cell transplantation in children with prognostically unfavorable AML. The study group included 18 pts at the age of 1–18. The disease status at the transplantation time was as follows: high risk AML in first remission (n=4, 22 %), more than two remissions (n=7, 39 %), no remission (n=4, 22 %), or secondary AML in remission (n=3, 17 %). All patients received reduced-intensity conditioning regimen followed by HSCT from haploidentical donors. Hematologic recovery occurred in 17 out of 18 pts in a mean time of 11 days and 12 days for WBC and platelets, respectively. One patient with no remission at the time of transplantation died from leukemia progression and infection with no signs of hematologic recovery. The regimen toxicity was mild and manageable. Acute GVHD of I/II and III degree occurred in 88 % and 6 % of pts, respectively. Chronic GVHD occurred in 85 % of pts, having been quite severe in one pt. The causes of death were infection (n=2, 11 %) or disease relapse/progression (n = 5, 28 %). Eleven pts (61 %) are still alive and disease-free. EFS is 57.5 % with a mean follow-up of 84 (1–144) months. TRM is 13.3 % with a mean follow-up of 124 months.

Keywords: pediatric acute myeloid leukemia, unfavorable prognosis, haploidentical hematopoietic stem cell transplantation.

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Successful allogeneic bone marrow transplantation in patients with severe gram-negative sepsis and septic shock

BONE MARROW TRANSPLANTATION , , , , , , , , , , , ,

G.M. Galstyan, P.M. Makarova, L.A. Kuzmina, Ye.N. Parovichnikova, G.A. Klyasova, O.S. Pokrovskaya, M.Yu. Drokov, V.A. Novikov, V.V. Troitskaya, I.E. Kostina, and V.G. Savchenko

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

ABSTRACT

We present two cases of successful allogeneic bone marrow transplantation in the patients with severe gram-negative sepsis and septic shock. The features of the post-transplantation period and management of patients are described.

Keywords: allogeneic hematopoietic stem cell transplantation, conditioning, sepsis, septic shock, post-transplantation period, neutropenic enterocolitis, prolonged neutropenia, Pseudomonas aeruginosa, acute respiratory failure, invasive pulmonary aspergillosis, invasive lung ventilation, noninvasive ventilation, mesenchymal stromal cells.

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Stable donor hematopoiesis reconstitution after post-transplantation relapse of acute myeloid leukemia in patient with inv(3)(q21q26), –7 and EVI1 oncogene overexpression treated by donor lymphocyte infusions and hypomethylating agents

BONE MARROW TRANSPLANTATION , , , , , ,

N.N. Mamaev, A.V. Gorbunova, T.L. Gindina, O.A. Slesarchuk, V.N. Ovechkina, S.N. Bondarenko, O.V. Goloshchapov, V.M. Kravtsova, and B.V. Afanasev

I.P. Pavlov Saint Petersburg State Medical University, R.M. Gorbacheva Institute of Pediatric Oncology, Hematology and Transplantology, Saint Petersburg, Russian Federation

ABSTRACT

We present the case of successful treatment of post-transplantation relapse of prognostically unfavorable AML with inv(3)(q21q26), –7 and EVI1 oncogene overexpression, when stable donor hematopoiesis reconstitution was achieved due to one high-dose cytarabine course, DLI, and hypomethylating agents (decitabine, 5-azacitidine). Possible molecular mechanisms of this effect are discussed with respect to the new approaches to management of such patients.

Keywords: acute myeloid leukemia, inv(3)(q21q26), EVI1 high expression, hematopoietic stem cell transplantation, relapse, treatment, donor lymphocyte infusions, hypomethylating agents.

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REFERENCES

  1. Мамаев Н.Н., Горбунова А.В., Гиндина Т.Л. и др. Лейкозы и миелодис- пластические синдромы с высокой экспрессией гена EVI1: теоретические и клинические аспекты. Клин. онкогематол. 2012; 5(4): 361–4.[Mamayev N.N., Gorbunova A.V., Gindina T.L. et al. Leukemias and myelodisplastic syndromes with high EVI1 gene expression: theoretical and clinical aspects. Klin. onkogematol. 2012; 5(4): 361–4. (In Russ.)].
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  5. Pavletic S.Z., Kumar S., Mohty M. et al. NCI First International Workshop on the biology, prevention, and treatment of relapse after allogeneic hematopoietic stem cell transplantation: Report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biol. Blood Marrow Transplant. 2010; 16: 871–90.
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  7. Lubbert M., Bertz H., Wasch R. et al. Efficacy of a 3-day, low-dose treatment with 5-azacytidine followed by donor lymphocyte infusions in older patients with acute myeloid leukemia or chronic myelomonocytic leukemia relapsed after allografting. Bone Marrow Transplant. 2009; 45(4): 627–32.
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Impact of molecular genetic and cytogenetic characteristics on outcomes of allogeneic hematopoietic stem cell transplantation in chronic myeloid leukemia

BONE MARROW TRANSPLANTATION , , ,

A.V. Gorbunova, T.L. Gindina, E V. Morozova, I.M. Barkhatov, N.N. Mamayev, and B.V. Afanasyev

R.M. Gorbacheva Institute of Pediatric Oncology, Hematology and Transplantology, I.P. Pavlov State Medical University, Saint Petersburg, Russian Federation

ABSTRACT

Point mutations in the BCR-ABL kinase domain, BCR-ABL and EVI1 gene expression alterations, and additional chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia are strongly associated with resistance to tyrosine kinase inhibitors (TKIs) and disease progression, but their effect on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is uncertain. This retrospective study included 35 CML patients with resistance to TKI therapy who received a related or unrelated HSCT. Additional chromosomal aberrations were associated with the decreased rate of the complete molecular response (CMR) after allo-HSCT. EVI1 expression level was associated with a decreased disease-free survival (DFS). BCR-ABL kinase domain mutations showed no influence on CMR, OS, and DFS in this patient cohort. 9 out of 10 patients with T315I mutation achieved CMR. EVI1-directed stratification of patients during the post-transplantation period may improve outcome of HSCT.

Keywords: chronic myeloid leukemia, CML, allogeneic hematopoietic stem cells transplantation, allo-HSCT, BCR-ABL, EVI1.

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Refernces

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  8. Burchert A., Wang Y., Cai D. et al. Compensatory PI3-kinase/Akt/mTOR activation regulates imatinib resistance development. Leukemia 2005; 19: 1774–82.
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Hematopoietic stem cell transplantation in AML patients with t(8;21)(q22;q22) translocation

BONE MARROW TRANSPLANTATION , , ,

N.N. Mamayev, A.V. Gorbunova, T.L. Gindina, I.M. Barkhatov, S.N. Bondarenko, M.Yu. Averyanova, О.V. Pirogova, O.V. Goloshchapov, Ye.V. Kondakova, and B.V. Afanasyev

R.M. Gorbacheva Institute of Pediatric Oncology, Hematology and Transplantology, I.P. Pavlov State Medical University, Saint Petersburg, Russian Federation

ABSTRACT

The outcomes of bone marrow transplantation for treatment of relapses in 7 AML patients with t(8;21)(q22;q22) translocation are presented and analyzed. Two of them were transplanted in the 1st remission, and 5 patients received HSCT during resistance to the therapy. Three patients underwent unrelated allo-HSCT with various sources of HSC. Three others were treated with related allo-, auto-, or haplo-HSCT, respectively. In the last patient, auto-HSCT followed by related haplo-HSCT was performed. The course of disease was monitored using the serial levels of both AML1-ETO and WT1 gene expression. The high AML1-ETO levels and t(8;21) translocation were detected in all studied patients, whereas no FLT3 gene mutations were found in any patients, and a classic V617F JAK2 mutation was present in 1 patient. The levels of AML1-ETO and WT1 gene expression decreased in parallel with the relapse reduction in 2 patients, but remained elevated in 3 other patients despite the normalization of bone marrow morphologic picture, including 2 cases of development of extramedullary AML relapses. Relapses were accompanied by the high levels of the above gene expression. The study led to the conclusion that bone marrow transplantation is indicated for some AML patients with t(8;21) translocation. The treatment efficacy can be monitored using serial measurements of WT1 gene expression levels.

Keywords: AML with t(8;21) translocation, bone marrow transplantation, AML1-ETO and WT1 gene expression monitoring, molecular monitoring during treatment of leukemia.

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Mixed chimerism following allogeneic bone marrow transplantation: cases report

BONE MARROW TRANSPLANTATION , , , ,

K.N. Melkova, N.V. Gorbunova, T.Z. Cherniavskaya

FSBI «N.N. Blokhin Russian Cancer Research Center» RAMS, Moscow, Russian Federation

ABSTRACT

Cimerism monitoring after the bone marrow transplantation (BMT) by a method based on the quantitative polymerase chain reaction (PCR), is important for the assessment of efficiency of transplantation, early identification of recurrence and timely correction of therapy. Clinical examples of the mixed chimerism after allogeneic BMT are presented.

Keywords: allogeneic transplantation, chimerism, mixed chimerism, bone marrow, hematopoietic stem cells.

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REFERENCES

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Chimerism following allogeneic hematopoietic stem cell transplantation

BONE MARROW TRANSPLANTATION ,

O.V. Blau

Charité University School of Medicine, Department of Hematology and Oncology, Berlin, Germany

ABSTRACT

Allogenic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for various hematological disorders. Different molecular genetics methods are useful to monitor engraftment, relapse of the underlying disease, rejection of the graft, and minimal residual disease. Cytogenetic investigations, fluorescence in situ hybridization, PCR on chromosome abnormalities, lymphocyte-receptor gene rearrangement, and chimerism analysis are widely employed, although they are characterized by different sensitivity. Quantitative analysis of chimerism after HSCT is an important method for monitoring engraftment and allows discrimination between graft failure and relapse. This method appears to be adequate after reduced intensity conditioning (RIC) HSCT, when graft versus leukemia effect plays an important role in leukemia eradication. The use of lineage-specific chimerism analysis makes chimerism study more informative. Stable long-term complete chimerism correlates with complete hematological remission. Mixed chimerism is usually associated with relapse or graft failure. Prolonged mixed chimerism is a phenomenon in some patients after RIC with chronic lymphoproliferative disorders. This may be important to understand graft versus leukemia effect in such patients. Serial chimerism analysis is a suitable tool to evaluate efficacy of transplantation and early identification of relapse.

Keywords: allogenic hematopoietic stem cell transplantation, chimerism.

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