Alkylating Agents and Myeloid Cancer

I think all of us can agree, getting a second cancer while we are trying to deal with the first one is a real bitch, especially if the second cancer is caused by the therapy you are using to control the CLL in the first place. Myeloid cancer falls into that unlovely category.

There have been concerns voiced for several years now that some of our most potent combinations using alkylating agents (chlorambucil, cyclophosphamide, bendamustine) may increase the risk of secondary myeloid cancer. I wrote about this back in 2003, soon after I read an article by Dr. Kanti Rai. In his article Dr. Rai focused on the combination of fludarabine with chlorambucil.

That was then, chlorambucil was still widely used. Now we are in the age of FCR and Treanda (bendamustine). Since cyclophosphamide and bendamustine are both also classified as alkylating agents, same family as chlorambucil, is there increased risk of therapy related myeloid cancer after using either of these two chemotherapy agents?

Long term effects of cyclophosphamide therapy

The thing you have to realize about treatment related secondary cancers such as MDS is that they are not going to show their ugly faces a couple of days after you complete therapy. Long term follow-up is needed to document cases. ASH 2010 gives us one such long term assessment of using cyclophosphamide and its potential impact on development of myeloid cancer.

Increased Incidence of Therapy Related Myeloid Neoplasia (t-MN) After Initial Therapy for CLL with Fludarabine-Cyclophosphamide (FC) Vs Fludarabine (F): Long-Term Follow-up of US Intergroup Study E2997

Mitchell R Smith, MD, PhD1, Donna Neuberg, ScD2,Ian W. Flinn, MD, PhD3, Michael R. Grever, M.D.4,John M. Bennett, MD5, Gordon Dewald*,6, Elisabeth M Paietta, PhD7, Mark R. Litzow, MD8,Jacob M. Rowe9, David Lucas, PhD10, Shinichi Kitada, Ph.D.*,11, Diane F. Jelinek, PhD8,John G. Gribben, MD, DSc12, John C. Byrd, MD4, John C. Reed, MD, PhD13,Mohamad A. Hussein, M.D.*,14, Frederick R. Appelbaum, MD15, Richard A. Larson, MD16,Dennis F Moore, Jr, MD*,17 and Martin S. Tallman, MD18

Abstract 924

Background: Therapy-related myeloid neoplasia (t-MN), including myelodysplastic syndrome and acute myeloid leukemia, has been reported at a higher frequency with chlorambucil + fludarabine as compared to fludarabine alone, but has not been rigorously studied in the context of cyclophosphamide as an alkylator agent. The intergroupprospective randomized Phase 3 trial, E2997, compared FC with F alone as initial therapy for patients (pt) with chronic lymphocytic leukemia (CLL). FC therapy led to higher complete and overall response rates and longer progression-free survival at the initial analysis (Flinn et al JCO 2007). One rationale for combining F with C is that F can inhibit repair of DNA damage induced by C. FC did cause more myelosuppression that could lead to more long-term effects on myeloid hematopoietic function, including t-MN.

Methods: E2997 enrolled 278 pts, 141 on FC and 137 on F. These cases were assessed for t-MN by required reporting of these events. Baseline genetic and molecular features of CLL were available through a companion lab correlative trial for 235 pts, 122 on FC and 113 on F.

Results: With median follow-up of 6.4 yrs, there have been 13 (4.7%) reported cases of t-MN, 9 after FC and 4 after F. By cumulative incidence methodology, adjusting for the competing risk of death, the rates of t-MN at 7 yr are 8.2% after FC and 4.6% after F (p=0.18 by the Gray test). Median age at study entry of the t-MN pts was 60 (range 45–80) yrs vs 61 (range 33–86) yrs among those not reported to have t-MN. Median time from initial therapy to diagnosis of t-MN was 5 (range 0.7–8) yrs and did not differ between FC and F. Ten of 13 affected pts received 6 chemotherapy cycles. Additional therapy prior to occurrence of t-MN was given to only 2 of 9 FC pts, in contrast to 3 of 4 F pts. Thus, t-MN occurred in only 1 pt treated with F and no further therapy vs 7 who received FC and no further therapy. Ten of 12 pts with available cytogenetics at diagnosis of t-MN had an abnormality of chromosome 5 and/or 7, common to alkylating agent-induced t-MN, usually (n=8) with complex karyotype. Of the 9 pts with t-MN after FC, all 7 with available CLL data had lower risk IgVH mutated disease, in contrast to 1 of 4 with t-MN after F and 44% in the entire cohort.

Conclusion: Our analysis suggests that a higher incidence of t-MN has occurred after FC than after F. t-MN after FC occurred most often without additional therapy and in IgVH mutated CLL which is associated with more favorable outcome. The increased incidence of t-MN after FC in this study, usually in the absence of additional treatment, suggests that FC is more leukemogenic than F. This finding emphasizes a need for longer follow-up of toxicity and survival before concluding that FC is preferable to F as the chemotherapy backbone for initial therapy of both low and high risk CLL.

What is myeloid cancer?

I guess we need to know what myeloid cancer is, before we can decide whether or not to worry about it. You can refresh your memory of myelodysplasia (MDS) and full fledged myeloid cancer (AML - acute myelogenous leukemia) by visiting our previous article on the subject.

It is generally accepted that one of the causes of MDS is exposure to environmental toxins such as benzene or radiation. Workers in some industries such as the oil industry with heavy exposure to hydrocarbons have a slightly higher risk of contracting MDS. Males are slightly more frequently affected than females. Vietnam Veterans that were exposed to Agent Orange are at risk of developing MDS. But even if you never came within sniffing distance of Agent Orange or lived next to a petrochemical refinery, MDS can also be caused by inherent toxicity of many commonly used chemotherapy agents used to treat CLL. Looks like cyclophosphamide falls into the list of chemotherapy drugs that may cause therapy related myeloid cancers.

Does this mean you should never use cyclophosphamide?

It is important to look at the details before you jump to conclusions. This is a reasonably large group of patients, 278 of them, and they were followed for little over 6 years, on average. There were 13 cases of therapy related myeloid cancers. 9 of these were in the arm that F+C, compared to only 4 in the arm that got F alone. The risk of getting myeloid cancer was roughly twice as high in the F+C arm. It is also important to note that most often the patients had not received any other therapy to confuse the issue. Prognostics do not seem to matter, since folks with the good mutated form of IgVH were not spared either.

OK, this seems to be pretty solid information, even though the actual number of myeloid cancers observed was only 13 out of a total of 278 patients included in this study.

Frankly, I do not think it is a stretch to take this information about FC versus F and extrapolate it to FCR versus FR. I have yet to see similar long term study of this comparison for potential risk of myeloid cancers, but I am willing to bet dollars to donuts that patients getting FCR will be shown to have higher risk of treatment related myeloid cancers than FR. My anecdotal data-base of stories I hear from our members leans that way as well.

So, what else is new?  Don’t tell me you are surprised FCR is more toxic than FR.

Anyone out there thinks adding another drug to the FR regimen comes free of charge, no increase in toxicity? None of these drugs are the proverbial free lunch. You would be nuts to use any of them purely for recreational purposes. The more important question to ask yourself is this: what is to be gained by adding “C” to “FR”, is the risk worth the reward? That is what it boils down to, each and every time – weighing the risks and rewards.

Well, based on the recent German study that we reviewed earlier, if you have 11q deletion as your high risk FISH abnormality, you might be a good candidate for FCR, rather than FR. In your case the risk is outweighed by the reward of hopefully better response and longer remission with FCR than FR. How about the rest of the high-risk crowd? If you are 17p deleted folks, perhaps neither FR nor FCR are going to cut it for you, based on the results of the German study, and you had better look at other options.

How about the other end of the spectrum, the folks with the kinder and gentler 13q deletion only to deal with? If you are the type that looks at the half full glass, you may be inclined to look at the relatively small percentage of patients that got myeloid cancers after therapy, decide to take a chance on FCR in the hope of getting a really good remission for a nice long time. If on the other hand you are terrified of chemotherapy and they have to drag you kicking and screaming to the infusion chair, maybe you will settle for FR rather than FCR, just enough juice to take care of that silly little 13q deleted CLL.

While I am on the subject of cyclophosphamide

I am sure most of you will agree, dosage matters. It matters in efficacy, and it matters in toxicity. One of the facts I learned as I watched my husband go through his stem cell transplant is that they use boat loads of cyclophosphamide in many of the pre-conditioning regimens ahead of a transplant, even the so called “mini” transplants. All that cyclophosphamide has to be processed by the body, gotten rid of eventually. As you would expect, the drug and its breakdown products end up in your bladder. What happens if this nasty brew sits in your bladder for long hours because you did not want to get up and “go” so often? You guessed it, increased risk of damage to your bladder, something called “Hemorrhagic Cystitis”,  where you start peeing blood.  Trust me, not pretty. Moral of the story, be sure to drink lots of water before, during and after chemotherapy, and be very sure to go to the john and empty your bladder – every hour or so, damn the inconvenience.

J Natl Cancer Inst. 1995 Apr 5;87(7):524-30.

Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma.

Travis LB, Curtis RE, Glimelius B, Holowaty EJ, Van Leeuwen FE, Lynch CF, Hagenbeek A, Stovall M, Banks PM, Adami J, et al.

Epidemiology and Biostatistics Program, National Cancer Institute, Bethesda, Md, USA

BACKGROUND: Cyclophosphamide is an established bladder carcinogen, but few studies have examined the relationship between dose and effect. The largest analysis to date included only seven cases of bladder cancer. No investigation has estimated the risk of kidney cancer.

PURPOSE: The purpose of this study was to quantify the risk of bladder and kidney cancer following cyclophosphamide therapy.

METHODS: Within a cohort of 6171 two-year survivors of non-Hodgkin’s lymphoma (NHL), 48 patients with secondary cancer of the urinary tract were identified and matched to 136 control subjects with NHL who did not develop a second malignancy. Detailed information on chemotherapeutic drugs and cumulative dose received was collected for all subjects. Radiation dose to the target organ was estimated from individual radiotherapy records. Evaluations of the risk of second cancer as a result of treatment with cyclophosphamide alone, radiation alone, or both therapies were made relative to those patients who were exposed to neither treatment modality.

RESULTS: A significant 4.5-fold risk of bladder cancer (95% confidence interval [CI] = 1.5-13.6) followed therapy with cyclophosphamide, and risk was dependent upon cumulative dose. Among patients who received a total amount of cyclophosphamide of less than 20 g, a nonsignificant 2.4-fold risk of bladder cancer was apparent. Significantly elevated sixfold (95% CI = 1.3-29) and 14.5-fold (95% CI = 2.3-94) risks of bladder malignancy followed cumulative doses of 20-49 g and 50 g or more, respectively (P value for trend = .004). Radiotherapy given without cyclophosphamide was associated with a nonsignificant increased risk of bladder malignancy. Excess bladder cancer risk following treatment with both radiotherapy and cyclophosphamide was as expected if individual risks were summed. Neither radiotherapy nor cyclophosphamide was associated with excesses of kidney cancer.

CONCLUSIONS: Cyclophosphamide-related bladder cancer is dose dependent. For patients given cumulative doses between 20 and 49 g, the absolute risk of bladder cancer is on the order of three excess cancers per 100 NHL patients after 15 years of follow-up. At cumulative doses of 50 g or more, the excess risk increases to approximately seven excess bladder cancers per 100 NHL patients.

IMPLICATIONS: The strong dose-response relationship and high absolute risk of bladder cancer underscore the importance of limiting the cumulative dose of cyclophosphamide to what is required to achieve therapeutic end points. The risk of secondary bladder malignancy and other late sequelae of therapy must be carefully weighted against the curative gains provided by cyclophosphamide. Moreover, long-term side effects of therapy that might be acceptable in cancer treatment may need to be re-evaluated for patients with non-neoplastic disorders.

PMID: 7707439

How about bendamustine (Treanda)?

So far there seems reasonable agreement that using chlorambucil or cyclophosphamide may increase risk of myeloid cancers in a small percentage of patients. It also seems reasonable that increasing the cumulative dosages increases the risks. The third alkylating agent that has become popular in recent times is bendamustine. Does it carry a similar risk?

I am afraid so. Because bendamustine damages DNA, the same mechanism used by the other two alkylating agents as well,  there is a potential for treatment-induced development of secondary malignancies. Secondary malignancies have been reported in up to 4% of patients receiving bendamustine, including myelodysplastic syndrome, myeloproliferative disorders, chronic myelomonocytic leukemia. We brought to your attention recent FDA warnings on the subject several months ago.

Bottom line

Once again I want to reiterate for our readers the importance of making well informed therapy choices.

All of you know the bleak statistics of automobile accidents and the thousands of people who are killed on our highways each and every year. But that does not prevent you from driving, does it? On that score, you have little problem of weighing risks and rewards, the risk of getting killed in a traffic accident versus the reward of getting where you need to go - preferably in style. Hopefully, you further understand the importance of being sober while driving, since it reduces risk of becoming road-kill significantly.

This chemo stuff is no different. Understand the risks, talk to your doctor about your particular therapy choices, the dosages he thinks necessary, the precautions you should take to minimize the risks, and the rewards you can expect from the chosen therapy. Playing the hand you have been dealt to get best possible results is what this is all about, no one can do better than that.

With the holiday season fast approaching, be careful out there when you are driving.  A bad auto accident can kill you a lot faster than CLL or therapy related myeloid cancers.

Post script:

Dr. Terry Hamblin has just posted on his blog “Mutations of Mortality” covering much of the same concern regarding purine analog and alkylating agent combinations increasing risk of myeloid cancers.  You may want to look up his article dated Friday, January 7, 2011 titled “Treatment related MDS/AML in CLL”