Hematopoietic Cell Transplantation for Selected Leukemias

Number: 0640

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses hematopoietic cell transplantation for selected leukemias.

1. Medical Necessity

   Aetna considers the following interventions medically necessary:

   1. Allogeneic hematopoietic cell transplantation for the treatment of acute lymphocytic leukemia (ALL) when members meet the transplanting institution's selection criteria. In the absence of an institution's selection criteria, Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of ALL, including primary refractory ALL (i.e., leukemia that does not achieve a complete remission after conventional dose chemotherapy), except for members in refractory relapse, defined as persons in relapse who are unresponsive to 3 or more months of adequate chemotherapy.
   2. Non-myeloablative allogeneic hematopoietic cell transplantation, also known as mini-allograft or reduced intensity conditioning transplant, for the treatment of ALL for members with no persistent disease who meet all of the selection criteria above. Note: Persons with persistent disease should not be candidates for a mini-allograft transplant.
   3. Autologous hematopoietic cell transplantation for the treatment of acute myelogenous leukemia (AML) when members meet the transplanting institution's selection criteria. In the absence of an institution's selection criteria, Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of AML for any indication (e.g., first or second remission or relapsed AML if responsive to intensified induction chemotherapy) except as first-line treatment.
   4. Allogeneic hematopoietic cell transplantation (allo-HSCT) (ablative or mini-allograft) for the treatment of AML when members meet the transplanting institution's selection criteria. In the absence of an institution's selection criteria, Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of AML in any one of the following indications:
      
      
      1. Members who have relapsed following a prior autologous hematopoietic cell transplantation and who are medically able to tolerate the procedure; or
      2. Poor-risk to intermediate-risk AML in remission; or
      3. Primary refractory AML (i.e., leukemia that does not achieve a complete remission after conventional dose chemotherapy)
   5. A repeat allogeneic hematopoietic cell transplantation (ablative or mini-allograft) for the treatment of AML when members meet the transplanting institution's selection criteria. In the absence of an institution's selection criteria, Aetna considers a repeat allogeneic hematopoietic cell transplantation (ablative or mini-allograft) medically necessary when the first allogeneic hematopoietic cell transplantation was unsuccessful due to primary graft failure or failure to engraft or for persons who have relapsed after a prior hematopoietic cell transplantation.
   6. Allogeneic (ablative or non-myeloablative) hematopoietic cell transplantation for the treatment of chronic myelo-monocytic leukemia (CMML) and juvenile myelo-monocytic leukemia (JMML) when a matched or haploidentical donor is available;
   7. A repeat allogeneic (ablative or non-myeloablative) hematopoietic cell transplantation due to primary graft failure or failure to engraft for the treatment of CMML and JMML;
   8. Allogeneic (ablative or non-myeloablative) hematopoietic cell transplantation for T-cell prolymphocytic leukemia;
   9. Hematopoietic cell transplantation (allogeneic or autologous) as consolidation therapy of acute promyelocytic leukemia in second or subsequent remission;
   10. Allogeneic hematopoietic cell transplantation for the treatment of Richter syndrome (RS) when members meet the transplanting institution's selection criteria. In the absence of an institution's selection criteria, Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of members with RS who are physically fit, have adequate organ function, have a suitable HLA-compatible donor, and have responded to initial chemoimmunotherapy.
   11. Killer-cell immunoglobulin-like receptor (KIR) genotyping for evaluating HLA-matched donors for members with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation. Aetna considers KIR genotyping experimental and experimental for all other indications because its effectiveness for these indications has not been established.

2. Experimental and Investigational

   Aetna considers the following interventions experimental and investigational because the effectiveness of these approaches has not been established:

   1. Autologous hematopoietic cell transplantation for ALL
   2. Tandem (also known as sequential) transplants for the treatment of ALL
   3. A repeat allogeneic hematopoietic cell transplantation (ablative or mini-allograft) for members with persistent or progressive AML disease who have not been in remission
   4. A repeat autologous hematopoietic cell transplantation for AML
   5. Autologous hematopoietic cell transplantation for the treatment of CMML and JMML
   6. Hematologic stem cell micro-transplantation for AML
   7. Measurement of serum hepcidin levels for the management of members with acute leukemia or undergoing hematopoietic cell transplantation.

3. Related Policies

   • CPB 0494 - Hematopoietic Cell Transplantation for Non-Hodgkin's Lymphoma - for hematopoietic cell transplantation for chronic lymphocytic leukemia/small lymphocytic lymphoma
   • CPB 0634 - Non-myeloablative Hematopoietic Cell Transplantation (Mini-Allograft/Reduced Intensity Conditioning Transplant)
   • CPB 0674 - Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
Killer-cell immunoglobulin-like receptor (KIR) genotyping - no specific code
38205	Blood-derived hematopoietic cell harvesting for transplantation, per collection; allogeneic [ablative or non-myeloablative]
38206 - 38215	Transplant preparation procedures
38230	Bone marrow harvesting for transplantation; allogeneic
38232	autologous
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241	autologous transplantation
38242	Allogeneic lymphocyte infusions
86813	HLA typing; A, B or C multiple antigens
86817	DR/DQ, multiple antigens
86821	lymphocyte culture, mixed (MCL)
CPT codes not covered for indications listed in the CPB:
Hematologic stem cell micro-transplantation - No specific code
0251U	Hepcidin-25, enzyme-linked immunosorbent assay (ELISA), serum or plasma
Other CPT codes related to the CPB:
86920 - 86923	Compatibility test each unit
96401 - 96450	Chemotherapy administration code range
HCPCS codes covered if selection criteria are met:
S2150	Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency services, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition
ICD-10 codes covered if selection criteria are met:
C91.00 - C91.02	Acute lymphoblastic leukemia [ALL] [not covered for autologous transplantation]
C91.10 - C91.12	Chronic lymphocytic leukemia of B-cell type [Richter syndrome (RS)]
C92.00 - C92.02	Acute myeloblastic leukemia [not covered for repeat autologous transplantation]
C92.40 - C92.42	Acute promyelocytic leukemia
C92.50 - C92.52	Acute myelomonocytic leukemia
C92.60 - C92.62	Acute myeloid leukemia with 11q23-abnormality
C92.A0 - C92.A2	Acute myeloid leukemia with multilineage dysplasia
C93.00 - C93.92	Monocytic leukemia [CMML/JMML]
C94.20 – C94.22	Acute megakaryoblastic leukemia

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Background

Acute Lymphocytic Leukemia

Acute lymphocytic leukemia (ALL) is a heterogeneous group of malignancies arising from lymphocytic precursors.  The heterogeneity is related to whether the malignant clone is derived from a T or B cell as evidenced by the expression of different surface antigens.  The different subtypes of ALL are also heterogeneous with respect to response to chemotherapy and to the age distribution (i.e., different subtypes typically occur in either children or adults).  Acute lymphocytic leukemia has a bi-modal age distribution with an initial peak at 2 to 3 years, with the incidence again increasing after the age of 50.  By definition, ALL primarily affects the bone marrow, but in advanced cases, lymph nodes, liver, spleen and central nervous system (CNS) may be involved.  Although the cause of leukemia is not known in most patients, epidemiologic evidence suggests that genetics and environmental factors may play a role in its development. (Franeil et al, 2001)

Many studies have attempted to identify ALL patients at high-risk for relapse.  The curability of ALL is related to those prognostic factors identified by the peer-reviewed medical literature as follows: (Martin and Gajewski, 2001; NCI, 2002)

1. Age:

   In childhood ALL, conventional chemotherapy has been reported to achieve complete remission rates of about 95 % and 80 % can expect to survive 5 years.  The remission and long-term survival rates are reported to decline with age.  Several studies have correlated age over 35 or 50 years with shorter remission duration and decreased survival rates.  It has been reported that approximately 80 to 94 % of adult patients can expect to achieve complete remission rates after conventional chemotherapy and 20 to 40 % can expect to survive 2 years (NCI, 2002; Martin and Gajewski, 2001).

2. Immunologic subtype:

   Based on cell surface antigens, ALLs are subdivided according to the corresponding lymphocyte precursor.  About 80 % of cases of ALL in children and adults fall into the category of early pre-B cell ALL. Pre-B cell ALL, which lacks the expression of CD10 (also known as the common ALL antigen that is expressed in both B and T cell subtypes), is associated with chromosomal abnormalities, high white count and a poor prognosis.  Mature B cell ALL is histologically identical to Burkitt's lymphoma, the only distinction being that ALL involves primarily the bone marrow, while Burkitt's lymphoma involves primarily the lymph nodes.  While these entities are recognized as aggressive, their prognosis has improved recently with multi-agent chemotherapeutic regimens.  T-cell ALL is seen in about 10 to 15 % of ALL cases in children and adults.  T cell ALL is associated with male sex, older age, high white counts, CNS involvement and a mediastinal mass.  The lack of expression of CD10 in T-cell ALL is also associated with a poorer prognosis (NCI, 2002).

3. Cytogenetics:

   Certain cytogenetic abnormalities are associated with a poor prognosis.  The presence of the Philadelphia (Ph) chromosome or its molecular counterpart, the bcr-abl oncogene, is associated with a particularly poor prognosis.  The bcr-abl oncogene may be detectable only by pulse-field gel electrophoresis or reverse transcriptase polymerase chain reaction.  The presence of the Ph chromosome is more common in adult ALL, occurring in up to 30 % of cases, and thus may be partially responsible for the overall poorer prognosis in adult patients.  Two other chromosomal abnormalities with poor prognoses are t(4;11), and t(9;22).  In addition, patients with deletion of chromosome 7 or trisomy 8 have been reported to have a lower probability of survival at 5 years compared to patients with a normal karyotype (NCI, 2002).  In contrast, hyperdiploidy (i.e., more than 50 chromosomes) is associated with a favorable prognosis in children, but in adults the effect of this abnormality is less clear (Martin and Gajewski, 2001).

4. Response to induction therapy: 

   Initial chemotherapy promptly achieves a complete remission in most cases.  However, a prolonged time to reach complete remission is associated with a poor prognosis in all age groups.  Prolonged time to remission can be defined as either requiring 2 cycles of induction therapy, or greater than 4 weeks until complete remission of 5 % leukemic blasts in the bone marrow after 7 to 14 days of induction therapy (Martin and Gajewski, 2001).

5. Elevated white blood cell count:

   An elevated white blood count (WBC) is associated with a steadily worse prognosis.  Most studies define a WBC of more than 25,000 to 35,000 cells/uL as high-risk (Martin and Gajewski, 2001).

6. Miscellaneous factors:

   Other reported poor prognostic features include CNS involvement or extramedullary leukemia, hepatosplenomegaly, and lymphadenopathy (Martin and Gajewski, 2001).

It is considered an important goal in the management of ALL to identify patients that would preferentially benefit from either conventional chemotherapy or intensified therapy such as bone marrow transplant (BMT).  Patients with low-risk features have an excellent prognosis and are routinely treated with conventional chemotherapy.  In contrast, patients with one or more high-risk features have a poor response to standard chemotherapy.  In a large prospective study from Germany, the reported 5-year disease-free survival for adults with one or more high-risk features ranged from 11 % to 33 % (Hoelzer et al, 1988).  In many studies, these high-risk patients have been considered for BMT.  Bone marrow support can be derived from marrow stem cells harvested from either the bone marrow or peripheral blood from either an allogeneic, autologous or syngeneic (i.e., identical twin) donor.

Retrospective studies evaluating allogeneic transplantation for patients with ALL in first complete remission report higher treatment-related mortality and decreased disease relapse (Horowitz et al, 1991; Oh et al, 1998).  These effects appear to offset one another and to counteract any benefit from allogeneic transplantation in first complete remission (Martin and Gajewski, 2001).  In the largest prospective (n = 257) multi-center, randomized controlled trial to date (Sebban et al, 1994), adults with ALL in remission and who were younger than age 40 years received allogeneic BMT if a sibling donor was available or were randomly assigned to either ongoing chemotherapy or autologous BMT.  There was no advantage to allogeneic BMT for the group of patients with standard-risk ALL.  There was significant survival benefit, however, for patients with high-risk ALL (44 % versus 20 %).  The long-term survival of patients who received chemotherapy and autologous transplant was identical (NCI, 2002).

The International Bone Marrow Transplant Registry (IBMTR) reported a 38 % disease-free survival in Ph-positive patients in first complete remission receiving human leukocyte antigen (HLA)-matched transplants from sibling donors.  These results were similar to those of patients who were refractory to initial induction therapy or who were in second or subsequent remission (Barrett et al, 1992).  The Seattle Transplant Group has reported a 49 % disease-free survival at 2 years among 18 Ph-positive patients who received matched unrelated donor transplants (Sierra et al, 1997).

The majority of published studies consider allogeneic BMT a reasonable consideration for all high-risk (e.g., Ph-positive ALL, t(9;22), t(4;11), failure to respond to induction therapy, B-cell lineage with a white blood cell count greater than 30,000/uL) patients of suitable age (Martin and Gajewski, 2001).

Gaynon et al (2006) compared conventional sibling bone marrow transplantation (CBMT), BMT with alternative donor (ABMT), and chemotherapy (CT) for children with ALL and an early first marrow relapse.  After informed consent, 214 patients with ALL and early marrow relapse began multi-agent induction therapy.  A total of 163 patients with fewer than 25 % marrow blasts and count recovery at the end of induction (second complete remission [CR2]) were allocated by donor availability; and 50 patients with sibling donors were allocated to CBMT.  Seventy-two patients were randomly allocated between ABMT and CT while 41 patients refused allocation.  Overall, 3-year event free survival from entry is 19 % +/- 3 %.  Thirty-two of 50 CBMT patients (64 %) and 19 of 37 ABMT patients (51 %) underwent transplantation in CR2 with 3-year disease-free survival (DFS) of 42 % +/- 7 % and 29 % +/- 7 %.  The 3-year DFS is 29 % +/- 7 %, 21 % +/- 7 %, and 27 % +/- 8 % for patients allocated to CBMT, ABMT, and CT, respectively.  Contrary to protocol, 12 of 35 patients allocated to CT underwent BMT in CR2.  Of these, 5 patients died after BMT and 5 patients relapsed.  The authors concluded that over 50 % of patients died, failed re-induction, or relapsed again before 3 months after CR2 (median time to BMT).  Intent-to-treat pair-wise comparison of ABMT with CT, CT with CBMT, and CBMT with ABMT yields hazards of 1.2, 1.1, and 0.8 with p values of 0.56, 0.80, and 0.36, respectively.  Outcomes remain similar and poor for children with ALL and early marrow relapse.  Bone marrow transplantation is not a complete answer to the challenge of ALL and early marrow relapse.

Goldstone and colleagues (2008) prospectively evaluated the role of allogeneic transplantation for adults with ALL and compared autologous transplantation with standard chemotherapy.  Patients received 2 phases of induction and, if in remission, were assigned to allogeneic transplantation if they had a compatible sibling donor.  Other patients were randomized to chemotherapy for 2.5 years versus an autologous transplantation.  A donor versus no-donor analysis showed that Philadelphia chromosome-negative patients with a donor had a 5-year improved overall survival (OS), 53 % versus 45 % (p = 0.01), and the relapse rate was significantly lower (p < or = 0.001).  The survival difference was significant in standard-risk patients, but not in high-risk patients with a high non-relapse mortality rate in the high-risk donor group.  Patients randomized to chemotherapy had a higher 5-year OS (46 %) than those randomized to autologous transplantation (37 %; p = 0.03).  Matched related allogeneic transplantations for ALL in first complete remission provide the most potent anti-leukemic therapy and considerable survival benefit for standard-risk patients.  However, the transplantation-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk.  There is no evidence that a single autologous transplantation can replace consolidation/maintenance in any risk group.

A technology assessment of stem cell transplantation for ALL (IQWiG, 2007) found indirect evidence of prolonged survival from reduced-intensity stem cell transplantation in patients with refractory ALL.  The report found, however, that these results are limited by the small number of evaluable patients in clinical studies.  The report stated that the relevance of the type of donor remains unclear.  The report found no reliable evidence for superiority of non-myeloablative allogeneic stem cell transplantation (compared to myeloablative allogeneic stem cell transplant), or evidence of benefit from in-vitro manipulation of the graft in allogeneic or autologous stem cell transplantation (compared with transplantation without manipulation of the graft).  The report also found no additional benefit over chemotherapy of non-myeloablative therapy or autologous transplantation; however, available studies were not designed to evaluate non-inferiority (equivalence) of these types of stem cell transplantation to chemotherapy.  The report found, in patients with ALL and their subgroups, no evidence from direct comparative studies of a benefit over chemotherapy of allogeneic stem cell transplantation with an unrelated donor.  However, the available literature shows potential benefit, but also harm, from allogeneic stem cell transplantation with an unrelated donor versus chemotherapy for patients with ALL.

Acute Myelogenous Leukemia

Acute myelogenous leukemia (AML), also known as acute myeloid leukemia and acute non-lymphocytic leukemia, is a clonal disease characterized by the proliferation and accumulation of myeloid progenitor cells in the bone marrow, which ultimately leads to hematopoietic failure.  The incidence of AML increases with age, and older patients typically have worse treatment outcomes than do younger patients.  In patients with AML, there is an accumulation of leukemic blasts or immature forms in the bone marrow, peripheral blood, and other tissues, with a variable reduction in the production of normal platelets, mature red blood cells, and non-lymphocytic white blood cells (granulocytes, monocytes).  The increased production of malignant cells, along with reduction in these mature elements, result in a variety of systemic consequences including anemia, bleeding, as well as increased risks of infection.  The prognosis is poor for the majority of AML patients, based on age and/or adverse biologic features.  Standard therapy for AML is highly toxic and poorly tolerated, especially in the elderly, for whom few useful therapies exist.  Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important option for patients with high-risk AML during first complete remission (CR1), as well as for any patient in second or subsequent remission.  Use of reduced intensity conditioning transplantations (mini-allograft) has made allo-HSCT for a wider group of individuals (Stone et al, 2004; Stone, 2007; Robak and Wierzbowska, 2009).

Wahlin et al (2009) noted allo-HSCT from an HLA-identical sibling is recommended in standard and poor-risk patients, whereas unrelated donor transplant was reserved for poor-risk patients.  Autologous hematopoietic stem cell transplantation (auto-HSCT) is optional for standard or poor-risk patients who are ineligible for allo-HSCT.  Jones and Copelan (2009) stated that allo-HSCT provides the most powerful anti-leukemic effect in the treatment of AML.  Due to its significant morbidity and mortality, it should be used in CR1 patients whose relapse risk is substantial.  Reduced intensity transplantation is safer and extends the application of early transplantation to older patients and those with co-morbidities.  In patients with advanced disease, allo-HSCT provides a lower chance for cure, but is often the only curative treatment available.

Edenfield and Gore (1999) noted that allogeneic bone marrow transplantation (allo-BMT) as well as autologous bone marrow transplantation (auto-BMT) have become standard approaches for the management of adults with AML.  The indications for transplantation remain controversial as parallel improvements in intensive chemotherapy have resulted in excellent outcomes for many patients.  Allo-BMT is the therapy of choice for patients who fail to respond to induction chemotherapy.  For those patients in CR1, a policy of intensive post-remission chemotherapy with transplantation upon relapse appears to be optimal.  There are no data to support transplantation in CR1, allogeneic or autologous, for those patients with leukemia characterized by favorable cytogenetic abnormalities (i.e., core-binding factor type or t[15;17]), as these patients do well with non-myeloablative strategies.  Patients with relapsed disease appear to be best served with allogeneic transplantation from a HLA-matched sibling or one-antigen-mismatched family member, whereas for those patients lacking a related donor, unrelated donor allo-BMT or auto-BMT provides similar long-term overall survival.

Nathan and colleagues (2004) performed a meta-analysis to compare the effectiveness of auto-BMT with that of non-myeloablative chemotherapy alone (or no further treatment) in adults with AML.  Eligible studies were identified by searching electronic databases and by examining the reference lists of relevant studies and review articles.  Eligible studies were those that prospectively enrolled adults with AML and randomly assigned patients who were in CR1 and who did not have a matched sibling donor to one of the 2 consolidation therapies.  Two reviewers independently assessed all studies for relevance and validity.  They used a fixed-effects model to calculate the ratio of probabilities for DFS and OS at 48 months or at the nearest recorded assessment point for each study and for all studies combined.  All statistical tests were 2-sided.  These investigators identified 587 potentially relevant studies, 36 of which were retrieved for detailed evaluation.  In the 6 studies eligible for this meta-analysis, a total of 1,044 patients were randomly assigned to receive auto-BMT or non-myeloablative chemotherapy (5 studies) or auto-BMT or no further treatment (1 study).  Compared with patients who received chemotherapy or no further treatment, patients who received auto-BMT had a better DFS (ratio of disease-free survival probabilities = 1.24, 95 % confidence interval [CI]: 1.06 to 1.44; p = 0.006) but a similar overall survival (ratio of overall survival probabilities = 1.01, 95 % CI: 0.89 to 1.15; p = 0.86).  The authors concluded that these findings do not support the routine use of auto-BMT in adult AML patients in CR1.

Yanada et al (2005) stated that the effectiveness of allo-HSCT from a HLA-identical sibling donor remains controversial for patients with AML in CR1.  Because the karyotype identified at diagnosis is the most relevant prognostic factor for AML, it should be possible to assess the effectiveness more accurately on the basis of cytogenetic risk.  These researchers carried out a meta-analysis of 5 studies, which employed both natural randomization based on donor availability and intention-to-treat analysis, with OS as an outcome of interest.  Meta-regression analysis was then performed to identify the effectiveness for patients stratified into the favorable, intermediate, and poor cytogenetic risk groups.  For the entire cohort, there was a statistically significant advantage with allo-HSCT in terms of OS with a summary hazard ratio (HR) of 1.15 (95 % CI: 1.01 to 1.32, p = 0.037) for the random-effect model.  Meta-regression analysis showed a significant coefficient of +0.24 for the poor cytogenetic risk group, and -0.25 for the favorable cytogenetic risk group, indicating that the benefit of allo-HSCT was further increased for the former, and lost for the latter.  The coefficient for the intermediate cytogenetic risk group was +0.09, and was not statistically significant.  The authors concluded that these findings suggested that the effectiveness of allo-HSCT for patients with AML in CR1 depended on cytogenetic risk.  The beneficial effect of allo-HSCT was yielded for the poor-risk group, and probably for the intermediate-risk groups, but was absent for the favorable-risk group.

The Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON-SAKK) collaborative study group (Cornelissen et al, 2007) evaluated outcome of patients with AML in CR1 entered in 3 consecutive studies according to a donor versus no-donor comparison.  Between 1987 and 2004, a total of 2,287 patients were entered in these studies of whom 1,032 patients (45 %) without FAB M3 or t(15;17) were in CR1 after 2 cycles of chemotherapy, received consolidation treatment, and were younger than 55 years of age and therefore eligible for allo-HSCT.  An HLA-identical sibling donor was available for 326 patients (32 %), whereas 599 patients (58 %) lacked such a donor, and information was not available in 107 patients.  Compliance with allo-HSCT was 82 % (268 of 326).  Cumulative incidences of relapse were, respectively, 32 % versus 59 % for patients with versus those without a donor (p < 0.001).  Despite more treatment-related mortality (TRM) in the donor group (21 % versus 4 %, p < 0.001), DFS appeared significantly better in the donor group (48 % +/- 3 % versus 37 % +/- 2 % in the no-donor group, p < 0.001).  Following risk-group analysis, DFS was significantly better for patients with a donor and an intermediate- (p = 0.01) or poor-risk profile (p = 0.003) and also better in patients younger than 40 years of age (p <0 .001).  These investigators evaluated their findings and those of the previous MRC, BGMT, and EORTC studies in a meta-analysis, which revealed a significant benefit of 12 % in OS by donor availability for all patients with AML in CR1 without a favorable cytogenetic profile.

Craddock (2008) stated that allo-HSCT represents the most active form of anti-leukemic therapy in AML.  Advances in transplant technology and supportive care have resulted in improved outcomes in patients allografted using a myeloablative conditioning regimen.  At the same time the use of reduced-intensity conditioning regimens has allowed an immunologically mediated graft-versus-leukaemia effect to be exploited in older patients who were previously ineligible for transplantation on the grounds of age or co-morbidity.  This coupled with the increased availability of alternative stem cell sources, in the form of either unrelated or cord blood donations, has established allogeneic transplantation as a key therapeutic strategy in the treatment of both younger and older adults with AML.

Koreth and colleagues (2009) stated that the optimal treatment of AML in CR1 is uncertain.  Current consensus, based on cytogenetic risk, recommends myeloablative allo-HSCT for poor-risk but not for good-risk AML.  Allogeneic-HSCT, autologous transplantation, and consolidation chemotherapy are considered of equivalent benefit for intermediate-risk AML.  These researchers quantified relapse-free survival (RFS) and OS benefit of allo-HSCT for AML in CR1 overall and also for good-, intermediate-, and poor-risk AML.  Systematic review and meta-analysis of prospective trials evaluating allo-HSCT versus non-allo-HSCT therapies for AML in CR1 were carried out.  These researchers identified 1,712 articles.  Prospective trials assigning adult patients with AML in CR1 to undergo allo-HSCT versus non-allo-HSCT treatment(s) based on donor availability and trials reporting RFS and/or OS outcomes on an intention-to-treat, donor versus no-donor basis were identified.  Two reviewers independently extracted study characteristics, interventions, and outcomes.  Hazard ratios with 95 % CIs were determined.  Overall, 24 trials and 6,007 patients were analyzed (5,951 patients in RFS analyses and 5,606 patients in OS analyses); 3,638 patients were analyzed by cytogenetic risk (547, 2,499, and 592 with good-risk, intermediate-risk, and poor-risk AML, respectively).  Inter-study heterogeneity was non-significant.  Fixed-effects meta-analysis was performed.  Compared with non-allo-HSCT, the HR of relapse or death with allo-HSCT for AML in CR1 was 0.80 (95 % CI: 0.74 to 0.86).  Significant RFS benefit of allo-HSCT was documented for poor-risk (HR, 0.69; 95 % CI: 0.57 to 0.84) and intermediate-risk AML (HR, 0.76; 95 % CI: 0.68 to 0.85) but not for good-risk AML (HR, 1.06; 95 % CI: 0.80 to 1.42).  The HR of death with alloSCT for AML in CR1 was 0.90 (95 % CI: 0.82 to 0.97).  Significant OS benefit with allo-HSCT was documented for poor-risk (HR, 0.73; 95 % CI: 0.59 to 0.90) and intermediate-risk AML (HR, 0.83; 95 % CI: 0.74 to 0.93) but not for good-risk AML (HR, 1.07; 95 % CI: 0.83 to 1.38).  The authors concluded that compared with non-allo-HSCT therapies, allo-HSCT has significant RFS and OS benefit for intermediate- and poor-risk AML but not for good-risk AML in CR1.

Hartwig and colleagues (2009) noted that for patients with myeloid malignancies who relapse after allo-HSCT, one salvage option is a second allo-HSCT.  These researchers retrospectively analyzed outcomes of the second allo-HSCT in 25 patients who received at least 2 allografts from related/unrelated donors due to relapse of acute AML, myelodysplastic syndrome or myelofibrosis after the first allo-HSCT.  A minority of the AML/myelodysplastic syndrome patients had reached complete hematological remission before the second allo-HSCT (6/25, 24 %).  Reduced conditioning strategies were performed in the majority (n = 23).  Complete remission was achieved in all 21 cases with available data after the second allo-HSCT, but relapse was seen in 11/25 patients (44 %).  After a median follow-up of 18 months (range of 6 to 47), 8/25 patients (32 %) were still alive, and of those, 6 (24 %) were in stable remission.  In 9 cases mortality was associated to relapse, and in 8 cases to transplant-related causes (treatment-related mortality; 8/25, 32 %).  The authors concluded that a second allo-HSCT offers the chance of stable remission for some patients relapsing with a myeloid malignancy after a first allo-HSCT, although high treatment-related mortality and relapse rates remain a problem.

A technology assessment of stem cell transplantation for AML (IQWiG, 2007) found evidence from direct comparative studies demonstrated improved survival with non-myeloablative allogeneic stem cell transplantation with a related donor compared to conventional chemotherapy.  Indirect comparisons suggest improved OS in both non-myeloablative allogeneic stem cell transplantation with an unrelated donor over conventional chemotherapy in persons with refractory AML.  There was also evidence from indirect comparisons suggesting benefit of myeloablative allogeneic stem cell transplantation with an unrelated donor in persons with AML.  The assessment found insufficient evidence to draw conclusions about the comparative efficacy of transplants with related donors versus unrelated donors for AML.  The assessment found a lack of evidence comparing nonmyeloablative versus myeloablative stem cell transplant in AML.  There was also insufficient evidence that in-vitro manipulation of the graft improves outcomes of allogeneic or autologous transplantation in AML.

Acute Promyelocytic Leukemia

Sanz and Lo-Coco (2011) stated that the advent of all-trans-retinoic acid (ATRA) and its combination with anthracycline-containing chemotherapy have contributed in the past 2 decades to optimize the anti-leukemic effectiveness in acute promyelocytic leukemia (APL), leading to complete remission rates greater than 90 %, virtual absence of resistance, and cure rates of nearly 80 %.  Recently reported studies from large cooperative trials have also shown that more rational delivery of treatment and improved outcomes may derive from the use of risk-adapted protocols.  In particular, patients at higher risk of relapse (i.e., those presenting with WBC greater than 10 × 10(9)/L) seem to benefit from treatments that include cytarabine in the ATRA-plus-chemotherapy scheme, whereas patients with standard-risk disease can be successfully managed with less-intensive regimens that contain ATRA and anthracycline-based chemotherapy.  After the outstanding results with arsenic trioxide (ATO) in the treatment of APL relapse, several experimental trials have been designed to explore the role of ATO in front-line therapy with the aim not only of minimizing the use of chemotherapy but also to reinforce standard ATRA-plus-chemotherapy regimens and additionally improve therapeutic efficacy.  The authors noted that auto-HSCT and allo-HSCT can be used as consolidation therapy for APL.

In a review on “The evolving role of stem cell transplantation in acute promyelocytic leukemia”, Ramadan and colleagues (2103) stated that there is no role for stem cell transplantation in APL patients in CR1.  These investigators noted that auto-HSCT can be recommended for patients with prolonged (greater than 2 years) CR1 who test negative for minimal residual disease (MRD) after 2 cycles of ATO-based therapy, while patients ineligible for HSCT can continue ATO for consolidation and maintenance with close monitoring of MRD.  Patients who fail to achieve CR1, those who had short CR1, or those who test positive for MRD after ATO induction and consolidation, should be considered for allo-HSCT if a suitable donor is available. 

Holter Chakrabarty and colleagues (2104) identified favored choice of transplantation in patients with APL.  These investigators studied 294 patients with APL in CR2 receiving allogeneic (n = 232) or autologous (n = 62) HSCT including 155 with pre-HSCT promyelocytic leukemia protein/retinoic acid receptor-alpha (PML-RAR∝) status (49 % of allogeneic and 66 % of autologous).  Patient characteristics and transplantation characteristics, including TRM, OS, and DFS, were collected and analyzed for both uni-variate and multi-variate outcomes.  With median follow-up of 115 (allogeneic) and 72 months (autologous), 5-year DFS favored autologous with 63 % (49 % to 75 %), compared with allogeneic at 50 % (44 % to 57 %) (p = 0.10).  Overall survival was 75 % (63 % to 85 %) versus 54 % (48 % to 61 %) (p = 0.002), for auto-HSCT and allo-HSCT, respectively.  Multi-variate analysis showed significantly worse DFS after allo-HSCT (HR, 1.88; 95 % CI: 1.16 to 3.06; p = 0.011) and age greater than 40 years (HR, 2.30; 95 % CI: 1.44 to 3.67; p = 0.0005).  Overall survival was significantly worse after allo-HSCT (HR, 2.66; 95 % CI: 1.52 to 4.65; p = 0.0006); age greater than 40 (HR, 3.29; 95 % CI: 1.95 to 5.54; p < 0.001), and CR1 less than 12 months (HR, 1.56; 95 % CI: 1.07 to 2.26; p = 0.021).  Positive pre-HSCT PML-RAR∝ status in 17 of 114 allogeneic and 6 of 41 receiving autologous transplantation did not influence relapse, treatment failure, or survival in either group.  The survival advantage for autografting was attributable to increased 3-year TRM: allogeneic 30 %, autologous 2 %, and GVHD.  The authors concluded that auto-HSCT yielded superior OS for APL in CR2.

An UpToDate review on “Treatment of relapsed or refractory acute promyelocytic leukemia in adults” (Larson, 2014) states that “The treatment of patients with relapsed (or refractory) acute promyelocytic leukemia (APL) is generally aimed at achieving a second complete molecular remission with plans to proceed to high-dose chemotherapy and hematopoietic cell transplantation (HCT) in those with chemotherapy-sensitive disease.  Allogeneic HCT can be considered if a suitable donor is available, but for APL, allogeneic HCT is not clearly better than autologous HCT.  For patients who do not achieve RT-PCR [reverse transcription polymerase chain reaction] negativity, allogeneic HCT is the preferred treatment in eligible patients with an available donor”.

Chronic Myelo-Monocytic Leukemia and Juvenile Myelo-Monocytic Leukemia

Chronic myelo-monocytic leukemia (CMML) and juvenile myelo-monocytic leukemia (JMML) are malignancies as a consequence of over-production of monocytes and myelocytes (immature leukocytes) by the bone marrow.  Some of these blood stem cells never become mature leukocytes; and these immature leukocytes are known as blasts.  Over time, the monocytes, myelocytes, and blasts crowd out the reticulocytes and platelets in the bone marrow leading to infection, anemia, or easy bleeding.

Kroger et al (2002) reported the results of 50 allogeneic transplantations from related (n = 43) or unrelated (n = 7) donors, performed for CMML in 43 European centers.  The median age at transplant was 44 years (range of 19 to 61).  Eighteen patients had excess blasts ranging from 5 % to 30 % at the time of transplantation.  Two graft failures were observed (4 %).  Neutrophil (greater than 0.5 x 109/L) and platelet engraftment (greater than 50 x 109/L) was reached after a median of 17 days (range of 11 to 38) and 27 days (range of 11 to 48), respectively.  Acute graft-versus-host disease (GVHD grade II to IV was seen in 35 % of patients, while 20 % developed severe-acute GVHD grade III/IV.  Twenty-six patients (52 %) died of treatment-related causes.  After a median follow-up of 40 months (range of 11 to 110), the 5-year-estimated OS was 21 % (95 % CI: 15 to 27 %) and the 5-year estimated DFS was 18 % (95 % CI: 13 to 23 %).  Earlier transplantation in the course of disease, male donor, use of unmanipulated grafts, allogeneic transplantation and occurrence of acute GVHD favored better DFS, but did not reach statistical significance.  The 5-year estimated probability of relapse was 49 %.  The data showed a trend for a lower relapse probability of acute GVHD grade II to IV (24 % versus 54 %; p = 0.07), and for a higher relapse rate in patients with T cell-depleted grafts (62 % versus 45 %), suggesting a "graft-versus-CMML effect".

Kerbauy and co-workers (2005) evaluated the outcomes of allogeneic HSCT in 43 patients with CMML.  Patients were classified according to the French-American-British and World Health Organization classifications, as well as the International Prognostic Scoring System and the M.D.  Anderson prognostic score.  Co-morbidity scores were assessed by using an HSCT-specific co-morbidity index.  Patients were aged 1 to 66 years (median of 48 years).  Twenty-one patients received transplants from related donors (18 HLA-identical siblings and 3 HLA-non-identical family members), and 22 received transplants from unrelated donors (18 HLA matched and 4 HLA non-identical).  Several busulfan or total body irradiation (TBI)-based conditioning regimens were used.  Sustained engraftment was achieved in 41 patients.  Eighteen are alive at 1.9 to 14.1 years, for an estimated relapse-free survival of 41 % at 4 years.  Ten patients have relapsed, thus leading to a cumulative incidence of 23 % at 4 years.  Risk category by International Prognostic Scoring System, World Health Organization, M.D. Anderson prognostic score, or proliferative/dysplastic status had no statistically significant association with outcomes.  However, patients with higher co-morbidity scores had worse OS than patients with lower scores (p = 0.01).  There was a trend for a higher relapse incidence among patients at higher risk by the M.D. Anderson prognostic score.  These findings suggested that patients with few or no co-morbidities and those who undergo transplantation earlier in the disease course have the highest probability of successful outcome after allogeneic HSCT.

Elliott and colleagues (2006) reviewed their experience of allogeneic HSCT and donor lymphocyte infusions (DLI) for adults with CMML.  A total of 17 consecutive adults underwent allogeneic HSCT from related (n = 14) or unrelated (n = 3) donors.  Median age was 50 years (range of 26 to 60).  Seven patients (41 %) demonstrated relapse or persistent disease at a median of 6 months (range of 3 to 55.5).  Five patients underwent DLI for morphologic relapse and 1 for mixed donor chimerism.  Two patients achieved durable complete remissions of 15 months each.  The overall transplant-related mortality was 41 % (n = 7).  With a median follow-up of 34.5 months, 3 patients (18 %) currently remain alive and in continuous CR.  These findings demonstrated a graft-versus-leukemia effect in CMML, both for allogeneicHSCT and for DLI.  However, consistent with reported experience of others, overall outcomes remain less than optimal and unpredictable.

Krishnamurthy et al (2010) reported on single-center results of 18 patients with CMML who have undergone allogeneic HSCT.  The median age of patients was 54 years.  Seven patients had AML, which had transformed from CMML.  Overall, 11 patients received stem cells from an unrelated donor.  A total of 15 patients received a T-cell-depleted fludarabine/BU-based reduced-intensity conditioning HSCT.  The actuarial 3-year OS, non-relapse mortality (NRM) and relapse incidence for the cohort was 31 +/- 11 %, 31 +/- 14 % and 47 +/- 13 %, respectively.  Patients with favorable cytogenetics had a 3-year DFS of 65 +/- 17 %, whereas none of the 7 patients with intermediate-risk or poor-risk cytogenetics survived beyond 2 years (p < 0.01).  No patients with favorable risk cytogenetics died from NRM causes, while the 2-year NRM for the intermediate-risk/poor-risk cytogenetics subgroup was 71 +/- 22 % (p < 0.02).  In terms of disease status at transplantation, patients who had less than 5 % BM blasts had a 3-year DFS of 46.9 +/- 19 % compared with those with greater than 5% blasts at the time of transplantation (i.e., 20.0 +/- 13 %).  Recipient age, type of conditioning regimen or stem cell dose did not have a significant impact on overall outcomes.  These findings supported existing evidence that allogeneic HSCT is a feasible therapeutic option for CMML, with the ability to attain long-term remission among patient subgroups.

Cheng et al (2012) performed a literature search and reviewed available data for adult CMML patients undergoing HSCT.  The dearth of data that span 2 decades with changing transplant practices prohibited these researchers from performing a formal meta-analysis.  However, these investigators elected to present the current status of HSCT in adult CMML patients.  The authors concluded that carefully selected CMML patients may have the most benefit from this curative approach.

Woods and associates (2002) reported the first large prospective study of children with myelodysplastic syndrome (MDS) and JMML treated in a uniform fashion on Children's Cancer Group protocol 2891.  A total of 90 with JMML, various forms of MDS, or AML with antecedent MDS were treated with a 5-drug induction regimen (standard or intensive timing).  Patients achieving remission were allocated to allogeneic BMT if a matched family donor was available.  All other patients were randomized between autologous BMT and aggressive non-myeloablative chemotherapy.  Results were compared with patients with de novo AML.  Patients with JMML and refractory anemia (RA) or RA-excess blasts (RAEB) exhibited high induction failure rates and overall remission of 58 % and 48 %, respectively.  Remission rates for patients with RAEB in transformation (RAEB-T) (69 %) or antecedent MDS (81 %) were similar to de novo AML (77 %).  Actuarial survival rates at 6 years were as follows: JMML, 31 % +/- 26 %; RA and RAEB, 29 % +/- 16 %; RAEB-T, 30 % +/- 18 %; antecedent MDS, 50 % +/- 25 %; and de novo AML, 45 % +/- 3 %.  For patients achieving remission, long-term survivors were found in those receiving either allogeneic BMT or chemotherapy.  The presence of monosomy 7 had no additional adverse effect on MDS and JMML.  The authors concluded that childhood subtypes of MDS and JMML represent distinct entities with distinct clinical outcomes.  Children with a history of MDS who present with AML do well with AML-type therapy.  Patients with RA or RAEB respond poorly to AML induction therapy.  The optimum treatment for JMML remains unknown.

Baker and colleagues (2004) examined the effectiveness of allogeneic BMT without a TBI conditioning regimen in children with JMML.  A total of 8 patients with JMML (n = 6) or monosomy 7 (n = 2) underwent BMT at a median age of 20 months.  Donor source included fully matched related (n = 3), mis-matched related (n = 2), or fully matched unrelated (n = 3).  The conditioning regimen included busulfan (BU), cyclophosphamide (CY), and etoposide (VP16) (melphalan was substituted for VP16 in 1 patient).  The first patient in the series underwent TBI.  Graft-versus-host disease prophylaxis was with cyclosporin and methotrexate and in-vivo T-cell depletion (Campath 1 g) for mis-matched and unrelated transplants.  Seven and 2 patients, respectively, received chemotherapy and splenectomy before BMT.  At a median follow-up of 48 months after BMT, 5 patients remained in remission.  The OS rate was 63 % at 5 years.  All deaths occurred in patients with refractory disease at the time of BMT.  Allogeneic BMT without TBI appears to be effective therapy for JMML and avoids some of the potential late sequelae of TBI in pre-school children.

Korthof et al (2005) noted that JMML is a childhood leukemia for which allogeneic BMT is the only curative therapy.  These investigators performed 26 BMTs in 23 children (age of 0.5 to 12.7 years).  Conditioning was CY/TBI based (1980 to 1996, n = 14) or BU/CY/melphalan based (1996 to 2001, n = 9).  Donors were HLA-identical siblings (n = 11), unrelated volunteers (n = 9) or mis-matched family members (n = 3).  A total of 10 patients survive in CR (median follow-up of 6.8 years, range of 3.1 to 22.2 years).  Relapse or persistent disease was observed in 8 and 2 patients, respectively.  Nine of these patients died, 1 achieved a second remission following acute non-lymphatic leukemia chemotherapy (duration to date 5.3 years).  Transplant-related mortality occurred in 4 patients.  Overall survival at 5 and 10 years was 43.5 %.  Using T-cell-depleted, one-antigen mis-matched unrelated donors was the only significant adverse factor associated with relapse in multi-variate analysis (p = 0.039, HR 4.9).  Together with a trend towards less relapse in patients with GVHD and in patients transplanted with matched unrelated donors, this suggested a graft-versus-leukemia effect of allogeneic BMT in JMML.

Locatelli and associates (2005) stated that allogeneic HSCT is the only proven curative therapy for JMML.  The European Working Group on Childhood MDS (EWOG-MDS) and the European Blood and Marrow Transplantation (EBMT) Group reported the outcome of 100 children (67 boys and 33 girls) with JMML given unmanipulated HSCT after a preparative regimen including busulfan, cyclophosphamide, and melphalan.  Forty-eight and 52 children received transplants from an HLA-identical relative or an unrelated donor (UD), respectively.  The source of hematopoietic stem cells was bone marrow, peripheral blood, and cord blood in 79, 14, and 7 children, respectively.  Splenectomy had been performed before HSCT in 24 children.  The 5-year cumulative incidence of transplantation-related mortality and leukemia recurrence was 13 % and 35 %, respectively.  Age older than 4 years predicted an increased risk of disease recurrence.  The 5-year probability of event-free survival for children given HSCT from either a relative or a UD was 55 % and 49 %, respectively (p = NS), with median observation time of patients alive being 40 months (range of 6 to 144).  In multi-variate analysis, age older than 4 years and female sex predicted poorer outcome.  Results of this study compare favorably with previously published reports.  Disease recurrence remains the major cause of treatment failure.  Outcome of UD-HSCT recipients is comparable to that of children receiving transplants from an HLA-identical sibling.

Loh (2011) stated that JMML is an aggressive myeloid neoplasm of childhood that is clinically characterized by over-production of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung.  Juvenile myelo-monocytic leukemia is categorized as an overlap myeloproliferative neoplasms/myelodysplastic syndromes by the World Health Organization and also shares some clinical and molecular features with CMML, a similar disease in adults.  While the current standard of care for patients with JMML relies on allogeneic HSCT, relapse is the most frequent cause of treatment failure.

The Lymphoma and Leukemia Society (2009) noted that "Allogeneic stem cell transplantation is the only known curative option for JMML patients.  This treatment has been noted to achieve long-term survival in up to 50 % of patients but relapses are known to occur in up to 30 % to 40 % of patients after transplantation.  Second transplants have been beneficial for some patients".  The Lymphoma and Leukemia Society also noted that "Allogeneic stem cell transplantation has been used to treat and sometimes cure CMML patients".

The National Cancer Institute (2010) noted that "Bone marrow/stem-cell transplantation appears to be the only current treatment that alters the natural history of CMML".  Regarding JMML, the NCI (2010) noted that "No consistently effective therapy is available for JMML .... Bone marrow transplantation seems to offer the best chance for a cure".

The National Comprehensive Cancer Network (2010) clinical practice guidelines in myelodysplastic syndromes noted that "Allogeneic HSCT from an HLA-matched sibling donor is a preferred approach for treating a portion of patients with MDS.  Standard conditioning is used for relatively younger patients, while the approach using non-myeloablative conditioning is preferable in older individuals".

Intensified Chemotherapy and Allogeneic Hematopoietic Stem Cell Transplantation in Older Patients with Acute Lymphoblastic Leukemia

Fathi and colleagues (2016) stated that outcomes among older patients with acute lymphoblastic leukemia remain poor. In a phase II clinical trial, these researches determined the effectiveness  of an intensified, multi-agent approach derived from a Dana-Farber consortium trial in younger adults for patients older than 50 years.  The primary end-point was OS at 1 year.  Patients received induction chemotherapy with vincristine, prednisone, doxorubicin, and pegylated asparaginase.  Imatinib was incorporated for Philadelphia chromosome-positive disease.  After induction, the 1st consolidation incorporated clofarabine.  Patients in remission could proceed to allogeneic HCT after induction and consolidation I.  Those not receiving HCT went on to receive CNS, consolidation II, and continuation phases of treatment.  A total of 30 patients were enrolled: 19 achieved a CR after induction and 1 achieved CR after consolidation I for a CR rate of 67 %; 16 patients underwent HCT.  The proportion surviving at 1 year was 63 %, and this met the primary end-point.  The 2-year OS rate was 52 % (n = 30), and the 2-year DFS rate was 52 % for patients achieving CR (n = 20).  There was no survival advantage among those undergoing HCT.  Therapy-related hyperbilirubinemia prompted adjustments and limitations to asparaginase dosing.  The authors concluded that intensified chemotherapy can result in improved outcomes in comparison with historical data.  Moreover, they stated that additional studies of similarly intensive regimens are needed in this population.

Allogeneic Hematopoietic Cell Transplantation for the Treatment of Richter Syndrome

Richter syndrome (RS, also known as Richter transformation) is defined as the development of an aggressive large-cell lymphoma in the setting of underlying chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).  Although diffuse large B cell lymphoma (DLBCL) is the most common histology observed in patients with RT, Hodgkin lymphoma and T-cell lymphomas have also been reported less commonly (Brown, 2020).

Aulakh and colleagues (2020) stated that efficacy of conventional chemoimmunotherapy is limited in patients with Richter syndrome (RS) with anticipated median OS of less than 10 months; allo-HCT is commonly offered as a consolidative therapeutic option in RS.  To the authors’ knowledge, there are no RCTs that have compared allo-HCT against other therapies in RS; available allo-HCT data were limited to small case series from single-institution or registry studies.  These researchers carried out a systematic review and meta-analysis to examine the totality of evidence regarding the efficacy (or lack thereof) of allo-HCT for RS.  They extracted data on post-allograft outcomes related to benefits (overall response rate [ORR], CR, OS, and PFS).  For harms, data were extracted on NRM and relapse post-allografting.  The search strategy identified 240 studies, but only 4 studies (n = 72 patients) met inclusion criteria.  Pooled ORR, CR, OS, and PFS rates were 79 %, 33 %, 49 %, and 30 %, respectively.  Pooled NRM and relapse rates were 24 % and 28 %, respectively.  The authors concluded that findings of this systematic review and meta-analysis indicated that allo-HCT yielded encouraging OS in RS, thus remaining a reasonable therapeutic option in fit patients whose disease demonstrated a chemo-sensitive response to pre-transplant salvage therapies.  Moreover, these researchers stated that novel strategies are certainly needed to reduce the risk of relapse to further improve outcomes in these patients.

The authors stated that their analysis had several drawbacks, namely the small number of identified studies (n = 4) and a small number of patients per study.  Furthermore, in the absence of individual patient data, it was difficult to determine patients’ performance status (PS) and presence of specific co-morbidities to shed light into their fitness and ultimate impact on post-transplant outcomes.  Moreover, studies included in this systematic review/meta-analysis did not specify whether a clonal relation to CLL was confirmed in all patients who received an allo-HCT, or whether the intensity of the conditioning regimen impacted post-transplant outcomes.  In addition, clinical outcomes of 2 studies from the same institution were published in 2006 and 2015, raising concerns of possible overlapping of patients.  Also, these investigators did not identify any RCTs comparing allo-HCT with any other treatment modality in patients with RS.  Another main drawback was the absence of data evaluating the role of novel therapies, such as BCL-2 inhibitors like venetoclax when prescribed alone or in combination with other new agents in the studies included herein, consistent with contemporary practice.  Moreover, these researchers stated that notwithstanding the afore-mentioned drawbacks, allo-HCT remains a reasonable therapeutic option for patients with RS who are physically fit and have adequate organ function, have a suitable HLA-compatible donor, and demonstrate chemo-sensitive disease response prior to the procedure.  These cases should be referred to transplant centers as soon as possible to confirm eligibility for allo-HCT in a timely manner, considering the short-lived duration of responses with current chemo-immunotherapy regimens.

An UpToDate review on “Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma” (Brwon, 2020) states that “Since complete remissions after chemotherapy are short-lived, and long-term survivors have been reported following hematopoietic stem cell transplantation (HCT), we suggest nonmyeloablative allogeneic HCT when first remission has been achieved in most patients who are transplant candidates (Grade 2B).  Observation until progression is an acceptable alternative to consolidation with transplant for those in first remission after initial anthracycline-based combination chemotherapy if the DLBCL variant RT is clonally unrelated to the prior CLL, or if they are diagnosed simultaneously”.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Chronic lymphocytic leukemia/small lymphocytic lymphoma” (Version 4.2020) states that “Allogeneic HCT can be considered for patients with disease responding to initial chemoimmunotherapy”.

Killer-Cell Immunoglobulin-Like Receptor (KIR) Genotyping for Evaluating HLA-Matched Donors in Acute Myeloid Leukemia / Acute Lymphoblastic Leukemia

Cooley and colleagues (2010) stated that killer-cell immunoglobulin-like receptor (KIR) genes form a diverse, immunogenetic system.  Group A and B KIR haplotypes have distinctive centromeric (Cen) and telomeric (Tel) gene-content motifs.  Aiming to develop a donor selection strategy to improve transplant outcome, these researchers compared the contribution of these motifs to the clinical benefit conferred by B haplotype donors.  They KIR genotyped donors from 1,409 unrelated transplants for acute myelogenous leukemia (AML; n = 1,086) and acute lymphoblastic leukemia (ALL; n = 323).  Donor KIR genotype influenced transplantation outcome for AML but not ALL.  Compared with A haplotype motifs, centromeric and telomeric B motifs both contributed to relapse protection and improved survival, but Cen-B homozygosity had the strongest independent effect.  With Cen-B/B homozygous donors the cumulative incidence of relapse was 15.4 % compared with 36.5 % for Cen-A/A donors (relative risk [RR] of relapse 0.34; 95 % CI: 0.2 to 0.57; p < 0.001).  Overall, significantly reduced relapse was achieved with donors having 2 or more B gene-content motifs (RR 0.64; 95 % CI: 0.48 to 0.86; p = 0.003) for both HLA-matched and mis-matched transplants. The authors concluded that KIR genotyping of several best HLA-matched potential unrelated donors should substantially increase the frequency of transplants by using grafts with favorable KIR gene content.  These researchers stated that adopting this practice could result in superior DFS for patients with AML.

Bari, et al. (2013) tested the hypothesis that the clinical outcomes of allogeneic hematopoietic stem-cell  transplantation (HSCT) could be affected by donor KIR2DL1 polymorphism. Donor KIR2DL1 functional allele typing was retrospectively performed using single nucleotide polymorphism assay in all 303 pediatric patients who received allogeneic HSCT at a single institution. Patients who received a donor graft containing the functionally stronger KIR2DL1 allele with arginine at amino acid position 245 (KIR2DL1-R(245)) had better survival (P = .0004) and lower cumulative incidence of disease progression (P = .001) than those patients who received a donor graft that contained only the functionally weaker KIR2DL1 allele with cysteine at the same position (KIR2DL1-C(245)). The effect of KIR2DL1 allelic polymorphism was similar in patients with acute myeloid leukemia or acute lymphoblastic leukemia  among all allele groups (P ≥ .71). Patients who received a KIR2DL1-R(245)-positive graft with HLA-C receptor-ligand mismatch had the best survival (P = .00003) and lowest risk of leukemia progression (P = .0005) compared with those who received a KIR2DL1-C(245) homozygous graft.

Oevermann, et al. (2014) analyzed the influence of donor killer-cell immunoglobulin-like receptor (KIR) gene haplotypes on the risk for relapse and the probability of event-free survival (EFS) in children with acute lymphoblastic leukemia who received human leukocyte antigen-haploidentical transplantation of ex vivo T-cell-depleted  peripheral blood stem cells. The KIR gene haplotype was evaluated in 85 donors, and the KIR B content score was determined in the 63 KIR haplotype B donors. Patients transplanted from a KIR haplotype B donor had a significantly better EFS than those transplanted from a KIR haplotype A donor (50.6% vs 29.5%, respectively; P = .033). Moreover, a high donor KIR B-content score was associated with a significantly reduced risk for relapse (Log-rank test for trend, P = .026). The investigators concluded that these data indicate that KIR genotyping should be included in the donor selection algorithm for haploidentical transplantation in children with acute lymphoblastic leukemia with the aim of choosing, whenever possible, a KIR haplotype B donor with a high KIR B-content score.

Bao and associates (2016) noted that KIR group B profiles (Bx) and homozygous of centromeric motif B (Cen-B/B) are the most preferable KIR gene content motifs for HSCT.  The risk of transplant from Bx1 donors and the benefit of the presence of Cen-B (regardless of number) were observed for standard-risk AML/MDS patients in this 4-year retrospective study.  A total of 210 Chinese patients who underwent unrelated donor HSCT were examined.  Donor KIR profile Bx was associated with significantly improved OS (p = 0.026) and RFS (p = 0.021) and reduced NRM (p = 0.017) in AML/MDS patients.  A significantly lower survival rate was observed for transplants from Bx1 donors compared with Bx2, Bx3, and Bx4 donors for patients in 1st CR (n = 82; OS: p = 0.024; RFS: p = 0.021).  Transplant from donors with Cen-B resulted in improved OS (HR = 0.256; 95 % CI: 0.084 to 0.774; p = 0.016) and RFS (HR = 0.252; 95 % CI: 0.084 to 0.758; p = 0.014) in AML/MDS patients at standard risk.  However, this particular effect did not increase with a higher number of Cen-B motifs (cB/B versus cA/B; OS: p = 0.755; RFS: p = 0.768).  No effect was observed on high-risk AML/MDS, ALL/non-Hodgkin lymphoma (NHL), and chronic myelogenous leukemia (CML) patients.  The authors concluded that avoiding the selection of HSCT donors of KIR profile Bx1 was strongly advisable for standard-risk AML/MDS patients.  The presence of the Cen-B motif rather than its number was more important in donor selection for the Chinese population.

Hematologic Stem Cell Micro-Transplantation for Acute Myeloid Leukemia

Dholaria and associates (2017) noted that the anti-tumor effects of allo-SCT depend upon engraftment of donor cells followed by a graft-versus-tumor (GVT) effect.  However, pre-clinical and clinical studies have established that under certain circumstances, anti-tumor responses could occur despite the absence of high levels of durable donor cell engraftment.  Tumor response with little or no donor engraftment has been termed "micro-transplantation (MT)".  It has been hard to define conditions leading to tumor responses without donor cell persistence in humans because the degree of engraftment depends very heavily upon many patient-specific factors, including immune status and degree of prior therapy.  Likewise, it is unknown to what degree donor chimerism in the blood or tissue is needed for an anti-tumor effect under conditions of MT.  These researchers summarized some key studies supporting the concept of MT; and emphasized the importance of recent large studies of MT in patients with AML.  These AML studies provided the first evidence of the efficacy of MT as a therapeutic strategy and lay the foundation for additional pre-clinical studies and clinical trials that will refine the understanding of the mechanisms involved and guide its further development as a treatment modality.

Cornillon and colleagues (2020) stated that MT is based on injection of HLA-mismatched granulocyte colony stimulating factor (G-CSF) mobilized hematopoietic stem cells, in combination with chemotherapy but without use of conditioning regimen nor immunosuppressive drugs.  As a result, a transient micro-chimerism is induced without engraftment.  Its efficacy relies both on host immune system stimulation (recipient versus tumor) and on a graft versus tumor effect.  Data are scarce and concern mostly Asian patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS).  In comparison to conventional treatment without MT, higher complete remission rates and longer DFS and OS have been reported.  Safety appeared acceptable.  The most frequent adverse event (AE) is non-severe cytokine release syndrome.  Risk of GVHD remains very low.  These investigators summarized the published data and detailed the practical aspects of the procedure.  Current data are not strong enough to provide recommendations on indications.  Nevertheless, it appeared reasonable to propose MT to patients with AML or HR-MDS, regardless of age, presenting an indication for allo-SCT but ineligible for it.  The authors concluded that MT is still under investigation and rather be proposed within clinical trials.

Azacitidine for Preventing Relapse Following Hematopoietic Stem Cell Transplantation for Advanced Myeloid Malignancies

Pan et al (2022) noted that relapse is the leading cause of death from myeloid malignancies following allo-HSCT.  Azacitidine (AZA) has gained attention in recent years in the prophylaxis of relapsed refractory hematologic malignancies.  In a systematic review and meta-analysis, these researchers examined the effectiveness of AZA in preventing relapse following HSCT in patients with myeloid malignancies.  They examined available cohort studies regarding the application of AZA for prophylaxis of relapse following HSCT for advanced MDS and AML.  Databases were searched for relevant studies.  Endpoints included 2-year relapse rate, survival, relapse-related mortality, as well as the incidence of GVHD.  A total of 444 patients from 13 studies were included in this analysis.  The pooled estimate of the cumulative incidence of relapse after 2 years in enrolled patients was 25 % (95 % CI: 18 % to 33 %).  The pooled estimates of 2-year survival probabilities were 65 % (95 % CI: 50 % to 79 %).  The pooled cumulative incidence of relapse-related mortality was 28 % (95 % CI: 22 % to 34 %).  The pooled estimated incidence of acute and chronic GVHD, respectively, were 28 % (95 % CI: 22 % to 34 %) and 38 % (95 % CI: 27 % to 49 %).  The authors concluded that AZA administration was effective for relapse prevention following HSCT in myeloid malignancies.

Consolidative Hematopoietic Stem Cell Transplantation Following CD19 CAR-T Cell Therapy for Acute Lymphoblastic Leukemia

Guidelines on acute lymphoblastic leukemia from the National Comprehensive Cancer Network (NCCN, 2022) recommend consideration of HSCT for relapsed or refractory acute lymphoblastic leukemia after CAR-T therapy with brexucabtagene autoleucel (Tecartus).

In a systematic review and meta-analysis, Xu et al (2022) compared the safety and effectiveness of consolidative HSCT following CD19 chimeric antigen receptor T (CAR-T) therapy with non-HSCT in the treatment of ALL.  These investigators searched PubMed, Embase, Cochrane Library and Web of Science databases for clinical trials.  Pooled HRs for OS, relapse rate, and leukemia-free survival (LFS) as well as overall incidence rates for TRM, acute GVHD (aGVHD), chronic GVHD (cGVHD), and infections were calculated using Stata software.  They screened 3,441 studies and identified 19 eligible studies with 690 patients.  Among the patients who achieved CR after CD19 CAR-T therapy, consolidative HSCT was beneficial for OS (HR = 0.34, 95 % CI: 0.17 to 0.68, p = 0.003), the relapse rate (HR = 0.16, 95 % CI: 0.10 to 0.25, p < 0.001), and LFS (HR = 0.15, 95 % CI: 0.08 to 0.28, p < 0.001).  For patients who achieved MRD-negative (neg) CR after CD19 CAR-T therapy, consolidative HSCT was beneficial for OS (0.57, 95 % CI: 0.33 to 0.99, p = 0.045), the relapse rate (0.14, 95 % CI: 0.06 to 0.31, p < 0.001), and LFS (0.21, 95 % CI: 0.12 to 0.35, p < 0.001).  Regarding safety, these researchers calculated pooled incidence rates for TRM (8 %, 95 % CI: 0.02 to 0.15), aGVHD (44 %, 95 % CI: 0.23 to 0.67), cGVHD (36 %, 95 % CI: 0.17 to 0.56), and infections (39 %, 95 % CI: 0.03 to 0.83).  The authors concluded that compared with non-HSCT treatment, consolidative HSCT following CD19 CAR-T therapy for R/R B-ALL patients could prolong OS and LFS and reduce the risk of relapse; the incidence rates for AEs were acceptable.  Moreover, these researchers stated that more high-quality randomized controlled trials (RCTs) with longer follow-up durations are needed to avoid bias and further determine the effectiveness of consolidative HSCT in this scenario.

The authors stated that this meta-analysis had several drawbacks.  First, because few RCTs exist for CAR-T therapy due to its novelty, some bias may have been introduced because of the nature of this study.  Patients in the HSCT group may achieve better outcomes, partly because fitter patients were more likely to be chosen for transplant.  Measures were taken to reduce such bias.  For example, these investigators compared the HSCT versus non-HSCT groups based on both achieving CR or MRD-neg CR, a strategy that should reduce bias to a certain extent.  Second, the limited number of included studies and small sample sizes of several studies may have compromised the accuracy of these findings, also resulting in an unclear conclusion of the CD28 subgroup.  Third, the analysis was not sufficiently thorough because of incomplete information, including the age, pre-transplantation history, donor, timing, and conditioning therapy of each group.  Therefore, these researchers could not provide detailed recommendations for consolidative HSCT.  This study provided guidance for clinical practice and directions for future research.

Measurement of Serum Hepcidin Levels for the Management of Patients with Acute Leukemia or Undergoing Hematopoietic Cell Transplantation

Słomka et al (2022) noted that the association between hepcidin and acute leukemia (AL) or HCT in children and adults remains obscure.  In a systematic review, these investigators examined this potential relationship via a review of observational studies.  They carried out an electronic search of 3 databases (PubMed, Scopus, and Web of Science Core Collection) up to March 31, 2022; 2 independent reviewers examined the search results according to pre-determined inclusion and exclusion criteria, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.  Of the 3,607 titles identified, 13 studies published between 2008 and 2021 met the inclusion criteria.  Most studies included a moderate number of subjects and controls and used enzyme-linked immunosorbent assay (ELISA) to determine serum hepcidin levels.  There were 3 principal findings: First, serum hepcidin levels in patients with AL or undergoing HCT were increased compared to controls, regardless of the patient's age and the phase of disease treatment.  Second, AL therapy and HCT significantly influenced serum hepcidin levels.  Third, serum hepcidin may predict a worse outcome in patients with AL and post-HCT.  The authors concluded that this systematic review provided an overview of observational studies that dealt with the association of hepcidin with AL and HCT.  These researchers stated that although disturbances in iron metabolism are common in AL and HCT, and hepcidin appeared to play a cardinal role in their modulation, more extensive research is needed.

The authors stated that this study had several drawbacks due to heterogeneity of the studies, relatively low number of patients included in basic studies, lack of studies comparing other novel parameters of iron metabolism, lack of studies comparing children and adults, and lack of long-term analyses of survival outcomes.

Tyrosine Kinase Inhibitors Maintenance Therapy with or without Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (ALL) in First Complete Remission

In a systematic review and meta-analysis, Shahzad et al (2023) compared outcomes of tyrosine kinase inhibitor (TKI) maintenance therapy with or without allo-HSCT in Ph+ ALL in CR1.  These investigators carried out a literature search on PubMed, Cochrane, and Clinical trials.gov.  After screening 1,720 articles, 12 studies were included.  Proportions and odds ratios (OR) with 95 % CI were computed; I2 provided an estimate of the percentage of variability in results across studies that was due to real differences and not due to chance.  Of 1,039 patients, 635 (61 %) had TKI alone and 404 (39 %) patients had HSCT followed by TKI.  At 3 years, a trend towards poor OS (OR 0.67, 95 % CI: 0.39 to 1.15, I2 = 68 %), (DFS; OR 0.58, 95 % CI: 0.26 to 1.29, I2 = 76 %), and higher relapse rate (RR; OR = 2.52, 95 % CI: 1.66 to 3.83, I2 = 26 %) was observed with TKI alone compared to HSCT-TKI.  The authors concluded that although HSCT followed by TKI maintenance in Ph+ ALL has long been considered standard of care (SOC), the introduction of potent 3rd-generation TKIs and bi-specific T-cell engagers (e.g., blinatumomab) has markedly improved outcomes while sparing the need for HSCT in newly diagnosed patients.

Tyrosine Kinase Inhibitors has the Potential to Avoid HSCT in Treatment for Adults with Philadelphia Chromosome-Positive ALL

Xie et al (2023) stated that allo-HSCT as post-remission treatment is recommended for Ph+ ALL in current guidelines; however, comparisons of later generation TKIs plus chemotherapy with allo-HSCT have yielded similar outcomes.  In a meta-analysis, these investigators examined allo-HSCT in CR1 versus chemotherapy for adult Ph+ ALL in the nest-generation TKI era.  Pooled assessment of the hematologic as well as molecular complete response rates were carried out following 3-month TKI treatment; HRs were determined for DFS and OS benefit with allo-HSCT.  The effect of MRD status on survival benefit was also analyzed.  A total of 39 retrospective and prospective, cohort, single-arm studies involving 5,054 patients were included.  Combined HRs indicated that in the general population, allo-HSCT favorably influenced DFS and OS.  Achieving complete molecular remission (CMR) within 3 months after starting induction was a favorable survival prognostic factor regardless of whether the patient had undergone allo-HSCT.  Among the patients with CMR, survival rates in the non-transplant subgroup were comparable with those in the transplant subgroup, with the estimated 5-year OS of 64 % versus 58 % and 5-year DFS of 58 % versus 51 %, respectively.  The use of next-generation TKIs led to a higher proportion of patients achieving CMR (ponatinib 82 % versus imatinib 53 %), while improving survival in non-transplant patients.  The authors concluded that these novel findings suggested that combination chemotherapy plus nest-generation TKIs resulted in a comparable survival benefit as with allo-HSCT for MRD-negative (CMR) patients.  This study provided novel evidence for allo-HSCT indications for Ph+ ALL in CR1 in the next-generation TKI era.

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